The quality of economic evaluations of ultra-orphan drugs in Europe – a systematic review

Abstract

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...

Analysis of Orphan Drugs Marketed in Spain during the Period 2010- 2015: Epidemiological, Clinical and Economic Characteristics

“…The current study therefore analysed information from the economic evaluations issued by two institutions in the United Kingdom that are pioneers in evaluating efficiency and that serve as models for countries where routine evaluations are not yet available. The ICER data from the evaluation reports showed a wide range (−£13,295 to £1,232,654/QALY), which coincides with the findings of another published study [33].…”

Why we should care about ultra-rare disease

“…A critical step in generating data is to establish disease-specific registries including longitudinal data on all affected patients. SCHULLER et al [12] suggest that ideally registries would start before drugs are marketed, so as to produce data about the natural history of the disease. Accordingly, EU countries need to work in close cooperation.…”

“…This legislation requires that the pharmaceutical industry has a right to: 1) obtain protocol assistance at a reduced rate; 2) access the centralised authorisation procedure; 3) enjoy lower registration fees; and 4) benefit from 10 years of market exclusivity after registration [7,[10][11][12]. This has led to the authorisation by the European Medicines Agency of 124 new orphan drugs in the EU between 2000 and 2015, of which about one-third were for ultra-rare diseases (www.ema.europa.eu/ema/).…”

Are current ICER thresholds outdated? Valuing medicines in the era of personalized healthcare

“…Among cancer drugs, 45% had ICERs below $50,000/QALY and 70% below $100,000/QALY. Meanwhile, threshold ICERs based on reimbursement and coverage decisions range from £20,000/QALY in England to €80,000/QALY in the Netherlands [1,6]. While the simplicity and ease of application of the ICER threshold (to just about any drugs and health technologies) make it very appealing, one cannot escape the deficiencies of the QALY as an outcome measure, and the arbitrariness (of the derivation) of the threshold as illustrated in the case of $50,000/QALY in the USA [7].…”

“…affecting no more than 5 in 10,000 and 1 in 50,000 people, respectively [1]). Within the European Union (EU), 88 drugs have received market authorization from the European Medicines Agency (EMA), of which nearly one-third was granted in 2014 and 2015.…”