Modelling benefits, costs and affordability of a novel gene therapy in hemophilia A

Abstract The objective was to assess undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox;Roctavian®) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra®) in patients with severe Hemophilia A (HA) without FVIII-antibodies. Secondary, weWe also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (i.e., time until benefits begin to offset upfront payment). We constructed a A Markov-model was constructed to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII% over time were first estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII- and emicizumab-arms, bleeds were based on trial evidence. Evidence and assumptions were validated using via expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time-horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years atand lower costs, and was therefore dominant. Valrox’ base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus to emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modelling cost-effectiveness analysis Treatment of patients with HA in the Netherlands treated with valrox was estimated to resultresulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility to of incorporation ofmodelincorporate treatment durability was demonstrated and , as well as quantification of novel outcomes such as value-based pricing scenarios and break-even ti¬me. However, more work is needed to beter characterize uncertainties, define affordability and increase informativeness for decision making. Future work should aim to better characterize uncertainties and increase translation of early economic evaluationsmodelling to direct research efforts

Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder:results of a prospective multicenter clinical utility study in the Netherlands

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p &lt; 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.</p

Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity:A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers

OBJECTIVE: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands. STUDY DESIGN: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications. RESULTS: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients. CONCLUSION: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance

Cerebrospinal fluid leakage costs after craniotomy and health economic assessment of incidence reduction from a hospital perspective in the Netherlands

OBJECTIVES We aim to quantify the cost difference between patients with incisional cerebrospinal fluid (iCSF) leakage and those without after intradural cranial surgery. Second, the potential cost savings per patient when a decrease in iCSF leakage rate would be achieved with and without added costs for preventative measures of various price and efficacy are modelled. DESIGN Health economic assessment from a hospital perspective based on a retrospective cohort study. SETTING Dutch tertiary referral centre. PARTICIPANTS We included 616 consecutive patients who underwent intradural cranial surgery between 1 September 2017 and 1 September 2018. Patients undergoing burr hole surgery or transsphenoidal surgery, or who died within 1 month after surgery or were lost to follow-up were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES Outcomes of the cost analysis include a detailed breakdown of mean costs per patient for patients with postoperative iCSF leakage and patients without, and the mean cost difference. For the scenario analyses the outcomes are the potential cost savings per 1000 patients when a decrease in iCSF leakage would be achieved. RESULTS Mean cost difference between patients with and without iCSF leakage was €9665 (95%CI, €5125 to €14 205). The main cost driver was hospital stay with a difference of 8.5 days. A 25% incidence reduction would result in a mean cost saving of -€94 039 (95% CI, -€218 258 to -€7077) per 1000 patients. A maximum cost reduction of -€653 025 (95% CI, -€1 204 243 to -€169 120) per 1000 patients could be achieved if iCSF leakage would be reduced with 75% in all patients, with 72 cases of iCSF leakage avoided. CONCLUSIONS Postoperative iCSF leakage after intradural cranial surgery increases healthcare costs significantly and substantially. From a health economic perspective preventative measures to avoid iCSF leakage should be pursued

Drempelwaarde bij vergoeding van nieuwe medicatie : Doelmatigheidsonderzoek en modellering als onmisbare schakels

There is increasing discussion in the Netherlands about the introduction of a threshold value for the costs per extra year of life when reimbursing costs of new drugs. The Medicines Committee ('Commissie Geneesmiddelen'), a division of the Netherlands National Healthcare Institute ('Zorginstituut Nederland'), advises on reimbursement of costs of new drugs. This advice is based upon the determination of therapeutic value of the drug and the results of economic evaluations. Mathematical models that predict future costs and effectiveness are often used in economic evaluations; these models can vary greatly in transparency and quality due to author assumptions. Standardisation of cost-effectiveness models is one solution to overcome the unwanted variation in quality. Discussions about the introduction of a threshold value can only be meaningful if all involved are adequately informed, and by high quality in cost-effectiveness research and, particularly, economic evaluations. Collaboration and discussion between medical specialists, patients or patient organisations, health economists and policy makers, both in development of methods and in standardisation, are essential to improve the quality of decision making

Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies: a Systematic Review

Background: As the application of next generation sequencing (NGS) is moving to earlier stages in the diagnostic pipeline for primary immunodeficiencies (PIDs), re-evaluation of its effectiveness is required. The aim of this study is to systematically review the diagnostic yield of NGS in PIDs. Methods: PubMed and Embase databases were searched for relevant studies. Studies were eligible when describing the use of NGS in patients that had previously been diagnosed with PID on clinical and/or laboratory findings. Relevant data on study characteristics, technological performance and diagnostic yield were extracted. Results: Fourteen studies were eligible for data extraction. Six studies described patient populations from specific PID subcategories. The remaining studies included patients with unsorted PIDs. The studies were based on populations from Italy, Iran, Turkey, Thailand, the Netherlands, Norway, Saudi Arabia, Sweden, the UK, and the USA. Eight studies used an array-based targeted gene panel, four used WES in combination with a PID filter, and two used both techniques. The mean reported reading depth ranged from 98 to 1337 times. Five studies described the sensitivity of the applied techniques, ranging from 83 to 100%, whereas specificity ranged from 45 to 99.9%. The percentage of patients who were genetically diagnosed ranged from 15 to 79%. Several studies described clinical implications of the genetic findings. Discussion: NGS has the ability to contribute significantly to the identification of molecular mechanisms in PID patients. The diagnostic yield highly depends on population and on the technical circumstances under which NGS is employed. Further research is needed to determine the exact diagnostic yield and clinical implications of NGS in patients with PID

Pharmacy in transition : A work sampling study of community pharmacists using smartphone technology

INTRODUCTION: The nature of community pharmacy is changing, shifting from the preparation and distribution of medicines to the provision of cognitive pharmaceutical services (CPS); however, often the provision of traditional services leaves little time for innovative services. This study investigated the time community pharmacists spend on the tasks and activities of daily practice and to what extent they are able to implement CPS-related services in daily practice. METHODS: Self-reporting work sampling was used to register the activities of community pharmacists. A smartphone application, designed specifically for this purpose, alerted participants to register their current activity five times per working day for 6 weeks. Participants also completed an online survey about baseline characteristics. RESULTS: Ninety-one Dutch community pharmacists provided work-sampling data (7848 registered activities). Overall, 51.5% of their time was spent on professional activities, 35.4% on semi-professional activities, and 13.1% on non-professional activities. The proportion of time devoted to CPS decreased during the workweek, whereas the time spent on traditional task increased. DISCUSSION AND CONCLUSION: This study shows it is feasible to collect work-sampling data using smartphone technology. Community pharmacists spent almost half of their time on semi-professional and non-professional activities, activities that could be delegated to other staff members. In practice, the transition to CPS is hampered by competing traditional tasks, which prevents community pharmacists from profiling themselves as pharmaceutical experts in daily practice