Rare diseases represent a group of conditions affecting a very limited number of patients. Low profitability resulting from the small size of target population coupled with difficulties in conducting the research causes the lack of interest from the pharmaceutical industry. In order to promote research and development of medicines for rare diseases, a special ‘orphan’ legislation was introduced in a number of regions. These measures led to a significant increase in the number of approved orphan molecules. The high per patient cost of orphan drugs, as well the rapid growth of orphan drug sector, raised concerns regarding the sustainable funding of therapies for rare diseases. Rare cancers represent the majority of the current orphan drug market and are often associated with very high revenues. This chapter provides a review of orphan legislations and health technology assessment framework, analyses the position of oncology drugs on the orphan drug market and discusses future perspectives.

BACKGROUND: Recent network models of schizophrenia propose it is the consequence of mutual interaction between its symptoms. While cross-sectional associations between negative and positive symptoms are consistent with this idea, they may merely reflect their involvement in the diagnostic process. Longitudinal analyses however may allow the identification of possible causal relationships. The European Schizophrenia Cohort (EuroSC) provides data suitable for this purpose. METHODS: EuroSC includes 1208 patients randomly sampled from outpatient services in France, Germany and the UK. Initial measures were repeated after 12 and 24months. Latent variable structural equation modelling was used to investigate the direction of effect between positive and negative symptoms assessed with the Positive and Negative Syndrome Scale, controlling for the effects of depressed mood and antipsychotic medication. RESULTS: The structural model provided acceptable overall fit [chi(2) (953)=2444.32, P<0.001; CFI=0.909; RMSEA=0.046 (90% CI: 0.043, 0.048); SRMR=0.052]. Both positive and negative symptoms were persistent, and strongly auto-correlated. There were also persistent cross-sectional associations between positive and negative symptoms. While the path from latent positive to negative symptoms from T1 to T2 approached conventional levels of statistical significance (P=0.051), that from T2 to T3 did not (P=0.546). Pathways in the reverse direction were uniformly non-significant. CONCLUSIONS: There was no evidence that negative symptoms predict later positive symptoms. The prediction of negative symptoms by positive symptoms was ambiguous. We discuss implications for conceptualization of schizophrenic processes.

ABSTRACTIntroduction: Numerous real-world studies have compared non-vitamin K antagonist oral anticoagulants (NOACs) with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF). A meta-analysis was performed to synthesize the available evidence.Methods: Systematic searches were performed through 12/2016 to identify non-randomized NVAF studies comparing NOACs with VKAs, and reporting effectiveness, safety, or persistence.Results: Of 562 citations identified, 49, 79, and 18 compared rivaroxaban, dabigatran, and apixaban, respectively, with VKAs and were included. Compared with VKAs, rivaroxaban was associated with a reduced risk of ischemic stroke (IS) (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.75?0.93), intracranial haemorrhage (ICH) (HR = 0.69, 95% CI = 0.52?0.90), and non-persistence (HR = 0.62, 95% CI = 0.60?0.65). Dabigatran was associated with a significantly lower risk of IS (HR = 0.80, 95% CI = 0.65?0.98) and ICH (HR = 0.45, 95% CI = 0.36?0.58), but not for non-persistence (HR = 0.91, 95% CI = 0.53?1.55), compared with VKAs. Apixaban was associated with a lower risk of ICH than VKAs (HR = 0.41, 95% CI = 0.28?0.60), but was not different to VKAs in terms of IS (HR = 1.01, 95% CI = 0.87?1.17) or non-persistence (HR = 1.08, 95% CI = 0.81?1.45).Conclusion: NOACs appear to be at least as effective and safe as VKAs for stroke prevention in patients with NVAF.

The 2014 British Thoracic Society (BTS) and Scottish Intercollegiate Guideline Network (SIGN) guidelines recommend a stepwise approach to asthma management. We investigated the management of asthma in primary care in the UK to understand how real-world practice compares with BTS/SIGN guidelines. Asthma patients were identified from the UK Clinical Practice Research Datalink from September 2006 to August 2016. Aims were to classify patients according to BTS/SIGN steps, describe the proportion of patients transitioning between steps and describe patient demographics and clinical characteristics per group. Overall, 647,308 patients with asthma were identified (40,096 aged 5-11 years; 607,212 aged 12-80 years). Most treated patients were in step 1 or 2 (88.3% of children/67.5% of adults in December 2007; 83.0% of children/67.0% of adults in June 2016). Most patients remained within their treatment step within a 6-month interval (>78% of children and adults throughout the study duration). The proportion of patients stepping up and down reduced from the beginning of the study, although stepping down to step 1 was relatively common in both adults and children. Few patients had a recorded asthma review in the year before reference date (18.8% of children and 14.8% of adults). Although prescribing patterns meant that most patients remained within their treatment step throughout the study, we cannot be sure that this was because their disease was truly stable. The small proportion of patients stepping up/down and the lack of recorded asthma review suggest that patients may not be treated in accordance with BTS/SIGN guidelines.

BACKGROUND: Few of studies investigated the effect of antihypertensives among working population. We aimed to describe the impact of hypertension with and without antihypertensives on hospitalizations because of cardiovascular diseases (CVDs) in the Japanese working population. METHODS: This retrospective study included adults aged 40-64 years whose systolic and diastolic blood pressure (BP) readings taken between 2008 and 2015 were available in the Japanese claims database. Individuals were categorized as treated (T) or untreated (UT) depending on their hypertension treatment history. Time to first CVD-related hospitalization was compared among individuals with different BP levels using Cox models that included baseline characteristics with either baseline BP level or a time-dependent variable reflecting BP changes over time. RESULTS: Of 740,784 UT individuals (male: 61.9%, mean age: 47.9 years), 2,121 individuals were hospitalized due to a CVD over a 957.3-day average follow-up. Among 72,828 T individuals (male: 74.3%, mean age: 53.7 years), the corresponding figure was 470 individuals over an 813.4-day average follow-up. The risk of hospitalization increased with baseline hypertension severity among UT (hazard ratios [HRs] = 1.93, 2.82, and 6.32 for grade 1, grade 2, and grade 3, respectively; P < 0.0001, reference: optimal) but not among T individuals. UT individuals with hypertension at any given time had a significantly higher probability of hospitalization compared to nonhypertensive individuals (HR = 1.74, P < 0.0001). CONCLUSIONS: This study adds quantitative evidence on the impact of hypertension on the risk of CVD-related hospitalization in the Japanese working population. It suggests that antihypertensive treatment had beneficial effects in this relatively young, working population aged 40-64 years.

AIMS: To estimate the impact of anti-vascular endothelial growth factor (VEGF) agents on visual impairment and blindness avoided in patients with diabetic macular edema (DME) and on associated patient and caregiver productivity loss in Japan. METHODS: This study compared the impact of current care (estimated at 53.8% utilization of anti-VEGF agents using current data) with that of hypothetical care (characterized by a higher utilization of anti-VEGF agents [80.0%], as estimated by an expert panel) of DME patients. A population-based Markov model (two-eye approach) simulated visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) transitions over 5 years with DME treatments (intravitreal aflibercept, ranibizumab, and triamcinolone acetonide, and grid/focal laser) in patients with DME. Patient and caregiver productivity loss was determined using the human capital method. RESULTS: In total, 570,000 DME patients were included in the model over 5 years. Increased utilization of anti-VEGF agents resulted in 6,659 fewer cases of severe visual impairment (SVI; 26-35 ETDRS letters) or blindness (0-25 ETDRS letters) compared with the current care approach (26,023 vs 32,682 cases; 20.38% reduction) over this period. Increased utilization of anti-VEGF agents also contributed to productivity loss savings of yen12.58 billion (US $115.64 million) (i.e., 17.01%) at the end of year 5. The total overall saving over 5 years was yen45.83 billion (US $421.27 million) (13.45%). LIMITATIONS: Few Japanese data were available, and assumptions were made for some inputs. Vision changes dependent on the function of both eyes were not studied. Only intravitreal (not sub-Tenon’s) injections of triamcinolone were considered in this model. Direct costs were not considered. CONCLUSIONS: Increased utilization of anti-VEGF agents can reduce SVI and legal blindness in patients with DME in Japan. This would also be associated with substantial savings in patient and caregiver productivity loss.

AIMS: There have been no systematic literature reviews (SLRs) evaluating the identified association between outcomes (e.g. clinical, functional, adherence, societal burden) and Quality of Life (QoL) or Healthcare Resource Utilization (HCRU) in schizophrenia. The objective of this study was to conduct a SLR of published data on the relationship between outcomes and QoL or HCRU. MATERIALS AND METHODS: Electronic searches were conducted in Embase and Medline, for articles which reported on the association between outcomes and QoL or HCRU. Inclusion and exclusion criteria were applied to identify the most relevant articles and studies and extract their data. A summary table was developed to illustrate the strength of associations, based on p-values and correlations. RESULTS: One thousand and two abstracts were retrieved; 5 duplicates were excluded. 997 abstracts were screened and 95 references were retained for full-text screening. 31 references were included in the review. The most commonly used questionnaire, which also demonstrated the strongest associations (defined as a p < 0.0001 and/or correlation +/- 0.70), was the Positive and Negative Syndrome Scale (PANSS) associated with HCRU and QoL (the SF-36, the Schizophrenia Quality of Life questionnaire [S-QOL-18], the Quality of Life Scale [QLS]). Other robust correlations included the Clinical Global Impression - Severity (CGI-S) with QoL (EQ5D), relapse with HCRU and remission with QoL (EQ5D). Lastly, functioning (Work Rehabilitation Questionnaire [WORQ] and Personal and Social Performance Scale [PSP]) was found to be associated to QoL (QLS and Subjective Well-being under Neuroleptics Questionnaire [SWN]). LIMITATIONS: This study included data from an 11-year period and other instruments less frequently used may be further investigated. CONCLUSIONS: The evidence suggests that the PANSS is the clinical outcome that currently provides the most frequent and systematic associations with HCRU and QoL endpoints in schizophrenia.