Access and pricing of medicines for patients with rare diseases in the European Union: an industry perspective.

INTRODUCTION: The EU Orphan Regulation has successfully stimulated R&D of medicines for rare diseases, resulting in a substantial increase of orphan designations and authorized orphan medicinal products in the EU during last decade. Despite such advances, access to treatment across the 27 EU Member States is still highly variable. AREAS COVERED: We provide an overview of the current situation of patient access to orphan drugs in the EU. We discuss the EU policy landscape regarding joint assessment and pricing & reimbursement negotiations of medicinal products, price and sustainability of orphan drugs for health care systems, and the importance of Real-World Data and registry infrastructures for rare diseases. Additionally, we provide recommendations for areas of improvement throughout the lifecycle of orphan drugs, aiming to preserve a positive R&D climate for rare diseases in the EU and accelerate patient access. EXPERT OPINION: The EU needs to maintain a patient-centric pharmaceutical ecosystem that encourages long-term investments and rewards innovation in areas of high unmet medical need. Areas of potential improvement range from enhanced alignment of regulatory and HTA evidence requirements and use of specific value frameworks for the assessment of orphan drugs to the development of registry infrastructures and innovative performance-based pricing agreements.

Economic evaluations in European reimbursement submission guidelines: current status and comparisons.

This study aimed to review European national health-economic (HE) guidelines and to identify recent developments in guideline recommendations by comparing the findings with those of a review published in 2001. Guidelines were identified by searching websites of the Internal Society for Pharmacoeconomics and Outcomes Research (ISPOR) and government health insurance agencies, and by a literature review. National guidelines showed broad consistency in ranking clinical data sources and choice of comparators for HE analysis, but varied in recommended costs to be included, methods related to cost calculation and discounting. Many European countries have developed or revised national HE guidelines. The recommendations in these guidelines differ in some key aspects, limiting transferability of outcomes of HE evaluations.

Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland.

OBJECTIVES: To assess cost implications per patient, per year, and to predict the potential annual budget impact when patients with bone metastases secondary to solid tumours at risk of skeletal-related events (SREs) transition from zoledronic acid (ZA; 4 mg every 3-4 weeks) to denosumab (120 mg every 4 weeks) in Austria, Sweden and Switzerland. METHODS: Country specific costs for medication and administration, patient management and SREs (defined as pathologic fracture, radiation to bone, surgery to bone and spinal cord compression) were assessed over a 1-year time horizon. Drug administration and patient management costs were taken from available public sources. SRE costs were based on local unit costs applied to country specific healthcare resources obtained from a multinational retrospective chart review study. Due to lack of real world data for the included countries, SRE rates were derived from phase III clinical trials in patients with advanced cancer and bone metastases. These trials demonstrated that denosumab was superior to ZA in the reduction of SREs. RESULTS: Estimated total annual cost savings for each patient transitioned from ZA to denosumab varied by country and cancer type, ranging from €1583 to €2375 in Austria, from €1980 to €2319 in Sweden (9.1 SEK/€) and from €3408 to €3857 in Switzerland (1.2 CHF/€). Cost savings were mainly driven by the lower SRE related costs and lower administration costs of denosumab compared with ZA. CONCLUSIONS: Denosumab offers superior efficacy compared with ZA in patients with solid tumours and bone metastases. Cost savings are predicted in the Austrian, Swedish and Swiss healthcare systems following treatment transition from ZA to denosumab.

Assessment of the reliability and repeatability of landmarks using 3-D cephalometric software.

The aim of this study was to analyze the reliability and repeatability of identification landmarks using 3-D cephalometric software. Ten orthognathic patients were selected for this study and underwent the following protocol: 1. radiographic evaluation (CBCT technique); 2. stone casts; 3. photos; and 4. 3-D cephalometric evaluation. Twenty-one hard tissue landmarks and 14 cephalometric measurements were taken three times (T1, T2, and T3) on each patient, with an interval of one week by two experts in orthodontics (A, B). Standard deviation and Pearson's correlation coefficient were calculated to evaluate intra- and inter-observer repeatability. The results showed a strong correlation for both intra- and inter-observer Pearson's correlation coefficient (>0.7). The current preliminary study showed that the reliability and repeatability of the identification landmarks were very high if the 3-D cephalometric landmarks are defined correctly in the three planes of the space. Further evaluation is necessary to better define the 3-D cephalometric system.

Sensitivity of magnetic resonance imaging and computed axiography in the diagnosis of temporomandibular joint disorders in a selected patient population.

PURPOSE: The aim of this study was to compare sensitivity differences and interpretative agreement for magnetic resonance imaging (MRI) and computed axiography (CA) tracings in a patient population group with temporomandibular disorder (TMD). MATERIALS AND METHODS: A convenience sample of 173 patients (53 men, 120 women; mean age: 33.2 ± 2.6 years) diagnosed with TMD was selected for this study. Each patient underwent an evaluation as per the European Academy of Craniomandibular Disorders clinical form as well as MRI and CA. RESULTS: Use of the MRI results as the gold standard for the planned comparison led to the following observations: a CA sensitivity of 68% for joints without morphologic changes (so-called normal temporomandibular joints [TMJs]), sensitivity of 27% for those with disc displacement, and sensitivity of 8% for those with osteoarthritis. The kappa index, or agreement between the two examination methods, was weak for normal TMJs (0.16), acceptable for anterior disc displacement with reduction (0.28), little for anterior disc displacement without reduction (0.10), and very little for morphologic alterations (0.01). CONCLUSION: The sensitivity and agreement of the two examination methods was generally low. It was even worse when pathologic changes in the TMJ were more severe. MRI and CA are different examinations that could both be considered for severe TMD diagnosis.

How does comorbidity affect cost of health care in patients with irritable bowel syndrome? A cohort study in general practice.

BACKGROUND: Irritable bowel syndrome (IBS) is associated with other disorders (comorbidity), reduced quality of life and increased use of health resources. We aimed to explore the impact of comorbidity on cost of health care in patients with IBS in general practice. METHODS: In this cohort study 208 consecutive patients with IBS (Rome II) were recruited. Sociodemographic data, IBS symptoms, and comorbidity (somatic symptoms, organic diseases and psychiatric disorders) were assessed at baseline. Based on a follow up interview after 6-9 months and use of medical records, IBS and non-IBS related health resource use were measured as consultations, hospitalisations, use of medications and alternative health care products and sick leave days. Costs were calculated by national tariffs and reported in Norwegian Kroner (NOK, 1 EURO equals 8 NOK). Multivariate analyses were performed to identify predictors of costs. RESULTS: A total of 164 patients (mean age 52 years, 69% female, median duration of IBS 17 years) were available at follow up, 143 patients (88%) had consulted their GP of whom 31 (19%) had consulted for IBS. Mean number of sick- leave days for IBS and comorbidity were 1.7 and 16.3 respectively (p < 0.01), costs related to IBS and comorbidity were 954 NOK and 14854 NOK respectively (p < 0.001). Age, organic diseases and somatic symptoms, but not IBS severity, were significant predictors for total costs. CONCLUSION: Costs for health resource use among patients with IBS in general practice were largely explained by comorbidity, which generated ten times the costs for IBS.

Economic evaluation of tegaserod vs. placebo in the treatment of patients with irritable bowel syndrome: an analysis of the TENOR study.

OBJECTIVES: Tegaserod is effective, safe, and well-tolerated in the treatment of patients with irritable bowel syndrome (IBS) with constipation. The aim of this study was to assess, from a payer perspective, the cost-effectiveness of tegaserod in the treatment of IBS patients, based on the TEgaserod in NORdic region (TENOR) trial data. METHODS: Female and male patients (Rome II criteria) were randomized to receive tegaserod 6 mg b.i.d. or placebo for 12 weeks. Patients (247 tegaserod; 238 placebo) completed the EuroQol EQ-5D questionnaire at baseline, Week 4, and Week 12. A 12-week economic study was undertaken to assess the incremental cost-effectiveness ratio (ICER) of tegaserod in terms of cost per quality-adjusted life-year (QALY) gained. Cost-effectiveness acceptability curves were calculated to estimate the probability of tegaserod being cost-effective at different benchmark values of cost per QALY gained. RESULTS: By assuming a daily drug cost to payers of Euro 2, Euro 3, and Euro 4, the ICER of tegaserod ranges between Euro 19,000 and Euro 38,000 per QALY gained, with the percentage of the bootstrap estimates below the willingness to pay level of Euro 50,000 per QALY gained ranging between 90% and 69%. CONCLUSIONS: This study established directly from a randomized controlled clinical trial that tegaserod is cost-effective in the treatment of non-D-IBS patients.

Performance of the EQ-5D in patients with irritable bowel syndrome.

OBJECTIVE: The EQ-5D is a standardized, nondisease-specific instrument for evaluating patients' preference-based valuations of health-related quality of life (HRQoL). This study's purpose was to determine the psychometric properties of EQ-5D in patients with irritable bowel syndrome (IBS). METHODS: Data from four European IBS studies were assessed: UK (n = 161 and n = 297), Spain (n = 503), and Germany (n = 100). The EQ-5D is a five-item health state descriptive system used to develop health states (EQ-5D(INDEX)) and a visual analog scale (VAS) (0-100 from worst to best imaginable health state, EQ-5D(VAS)). Measures used with the EQ-5D included the SF-36, Irritable Bowel Syndrome--Quality of Life (IBS-QOL), and both subjective and clinical global assessments of IBS. Convergent validity was assessed using SF-36 and IBS-QOL data, discriminant validity using global ratings of IBS severity, and responsiveness by subjective and physician assessment of condition. RESULTS: Moderate-to-high associations (r >or= 0.33) were seen between the EQ-5D(VAS) and the SF-36 and IBS-QOL subscales. Mean response scores to EQ-5D(INDEX) dimensions and the EQ-5D(VAS) score were significantly better for control patients than for patients with IBS (all P < 0.01). The EQ-5D(VAS) was able to discriminate between levels of pain severity (quartiles, P < 0.001; mild/moderate/severe, P < 0.05) and general health severity (mild/moderate/severe, P < 0.001). The EQ-5D(VAS) and the EQ-5D(INDEX) were responsive in patients using both a self-perceived (Subject's Global Assessment) and physician-rated (Clinic Global Assessment) improvement. CONCLUSIONS: The EQ-5D performs well in comparison to general and disease-specific outcomes. It is a valid and responsive measure that can be used to generate preference-based valuations of HRQoL in patients with IBS and useful for comparisons in clinical and cost-effectiveness studies.