Objective : To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods : A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations : Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions : While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

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Background: Psoriasis is a chronic, non-communicable, inflammatory skin disease with an extensive emotional and psychological impact on patients. While multiple treatment options are available, biological therapy is the treatment of choice for patients with moderate-to-severe psoriasis not responding to other systemic therapies. Multiple randomised controlled trials (RCTs) have compared the efficacy of biologics to placebo. However, the relative effectiveness of these treatments is not straightforward due to the lack of head-to-head evidence. Objectives: To compare the efficacy and safety of a new biologic netakimab and biologic agents approved and reimbursed in Russia (secukinumab, ustekinumab, infliximab, adalimumab, etanercept) in adults with moderate-tosevere plaque psoriasis. Methods: We performed the literature search in Pubmed database and Cochrane library, as well as in reference lists of original articles to identify publications of phase II, III, and IV RCTs evaluating the efficacy and safety of biologics for the treatment of moderate-to-severe psoriasis in adults. We assessed eligible RCTs for the risk of bias and possible sources of heterogeneity. Finally, we conducted a network metaanalysis using fixed effects model to synthesize evidence obtained from selected studies. Results: Overall, 20 articles were selected for quantitative and qualitative synthesis. Efficacy was determined by the proportion of patients achieving PASI75 at week 12 of the treatment. Safety was defined as the proportion of patients suffering at least one adverse event during the first 12 weeks of treatment. Network meta-analysis showed that netakimab is significantly more effective than adalimumab, etanercept, and ustekinumab, although there was no significant difference in efficacy between netakimab, secukinumab, and infliximab. In terms of safety, we found no statistically significant difference between all the interventions, except for etanercept, which was associated with lower safety profile. Conclusions: Obtained results suggest that netakimab has efficacy superior to or comparable with other biologics and a similar safety profile.

time, respectively. We assessed the impact of each medicine on patients' quality adjusted life-years (QALYs) and costs, consequently calculated the ICER (Incremental Cost Effectiveness Ratio). The costs were measured in dollar (1 dollar is equal to 42000 rials) with the perspective of payer. The discount rates were assumed 3% for utility and 5% for costs. Also, sensitivity analysis was conducted. Results: The costs are about 14163 dollars for Bosentan and 13876 dollars for Macitentan for each patient life time. The QALY produced per patient by Macitentan was 0.81 more than that of Bosentan. The calculated ICER was-15013959.37 which means that for each incremental QALY, the payer is charged less. Conclusions: Macitentan is preferable to and dominant over Bosentan in both effectiveness and expenditure. Thus, therapeutic regimen containing Macitentan is introduced as a favorable treatment strategy.

Background: HER2+ tumors make up approximately 20% of MBCs. The survival outcomes for HER2+ MBC patients improved significantly in the last decade due to the development of HER2-targeted therapies. The objective of this SLR was to assess recent evidence on the burden of HER2+ MBC.Methods: A SLR was conducted in MEDLINE and EMBASE databases (2010-2020) and congress abstract repositories (2018)(2019)(2020). The search adhered to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 8,115 records were identified, of which 6,549 were retrieved upon deduplication. Two reviewers independently screened titles and abstracts for eligibility. Fulltext review of 571 articles was then carried out.Results: 260 studies met the inclusion criteria. Seven sources of which compared HER2+ mBC patients to the general and BC populations reporting impaired health utility scores and moderate or worse health status. This was assessed using a variety of tools, such as EQ-5D-5L, FACT-B and EORTC QLQ-C30. In addition to lower Quality of Life (QoL), the disease is associated with impairment of work-and daily activity, negative body image perception, and mental disorders. The symptoms, comorbidities and treatment adverse events most frequently reported by HER2+ mBC patients include tiredness, decreased sexual interest, lack of energy, sore muscles, worry, difficulty sleeping and joint pain. Due to the longer treatment duration and high treatment costs of anti-HER2 treatments, HER2+ MBC leads to greater costs than other types of mBC. In Europe, overall-per-patient costs of HER2+ mBC per patient were V235,238-V269,749, of which V37,431-53,950 were annual treatment costs. Costs are primarily driven by treatment and hospitalization costs, and accumulatively increase by line of treatment.Conclusions: With improvements in disease management being made in recent years, the SLR demonstrated that a substantial burden of HER2+ MBC on patients' QoL and on the healthcare systems still exists, highlighting the need for more cost-effective treatment options.