5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Applying GRADE Criteria to Clinical Inputs to Cost-Effectiveness Modeling Studies.

BACKGROUND: Concerns have been raised about the use of clinical data in cost-effectiveness models. The aim of this analysis was to evaluate the appropriate use of data on clinical effectiveness in cost-effectiveness modeling studies that were published between 2001 and 2015. METHODS: Assessors rated 72 modeling studies obtained from three therapeutic areas by applying criteria defined by the Grading of Recommendations Assessment, Development and Evaluation group for assessing the quality of clinical evidence: selection of clinical data (publication bias), imprecision, indirectness, inconsistency (i.e., heterogeneity), and study limitations (risk of bias). For all parameters included in the analyses, potential changes over time were assessed. RESULTS: Although three out of four modeling studies relied on randomized controlled trials, more than 60% of the modeling studies were based on clinical data with a high or unclear risk of bias, in more than 80%, a risk of publication bias was found, and in about 30%, evidence was based on indirect clinical evidence, having significantly increased over the years. Study limitations were inadequately described in more than one third of the studies. However, less than 10% of clinical studies showed inconsistency or imprecision in study results. CONCLUSION: Despite the fact that the majority of economic evaluations are based on precise and consistent randomized controlled trials, their results are often affected by limitations arising from methodological shortcomings in the underlying data on clinical efficacy. Modelers and assessors should be more aware of aspects surrounding the quality of clinical evidence as considered by the Grading of Recommendations Assessment, Development and Evaluation group.

Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17,979 per QALY (€15,773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone.

Cost effectiveness of rivaroxaban for stroke prevention in German patients with atrial fibrillation.

OBJECTIVE: The aim of this study was to assess the cost effectiveness of the novel fixed-dose anticoagulant rivaroxaban compared with the current standard of care, warfarin, for the prevention of stroke in patients with atrial fibrillation (AF). METHODS: A Markov model was constructed to model the costs and health outcomes of both treatments, potential adverse events, and resulting health states over 35 years. Analyses were based on a hypothetical cohort of 65-year-old patients with non-valvular AF at moderate to high risk of stroke. The main outcome measure was cost per quality-adjusted life-year (QALY) gained over the lifetime, and was assessed from the German Statutory Health Insurance (SHI) perspective. Costs and utility data were drawn from public data and the literature, while event probabilities were derived from both the literature and rivaroxaban's pivotal ROCKET AF trial. RESULTS: Stroke prophylaxis with rivaroxaban offers health improvements over warfarin treatment at additional cost. From the SHI perspective, at baseline the incremental cost-effectiveness ratio of rivaroxaban was 15,207 per QALY gained in 2014. The results were robust to changes in the majority of variables; however, they were sensitive to the price of rivaroxaban, the hazard ratios for stroke and intracranial hemorrhage, the time horizon, and the discount rate. CONCLUSIONS: Our results showed that the substantially higher medication costs of rivaroxaban were offset by mitigating the shortcomings of warfarin, most notably frequent dose regulation and bleeding risk. Future health economic studies on novel oral anticoagulants should evaluate the cost effectiveness for secondary stroke prevention and, as clinical data from direct head-to-head comparisons become available, new anticoagulation therapies should be compared against each other.

Decision making in Germany: is health economic evaluation as a supporting tool a sleeping beauty?

For many years, the legal situation within the statutory health insurance (SHI) system in Germany has allowed for health economic evaluations. There are various reasons why health economic evaluations have played virtually no role in decision making until now: to begin with, a method for the evaluation of the relation between benefits and costs which needed to be in accordance with the legal requirements had to be developed, the outcome of which was the efficiency frontier approach. Subsequent health care reforms have led to changing objectives and strategies. Currently, price negotiations of newly launched drugs are based on an early benefit assessment of dossiers submitted by pharmaceutical manufacturers. Other reasons might be the presently very comfortable financial situation of the statutory health insurance system as well as a historically grown societal fear and discomfort towards what is perceived to be a rationing of medicinal products. For the time being, it remains open how long the German health care system can afford to continue neglecting the benefits of health economic evaluations for drug and non-drug interventions, and when it will be time to wake this sleeping beauty.