A systematic review on the appropriate discounting rates for the economic evaluation of gene therapies: whether a specific approach is justified to tackle the challenges?

OBJECTIVES: Discounting the cost and effect for health intervention is a controversial topic over the last two decades. In particular, the cost-effectiveness of gene therapies is especially sensitive to the discount rate because of the substantial delay between the upfront cost incurred and long-lasing clinical benefits received. This study aims to investigate the influence of employing alternative discount rates on the incremental cost-effectiveness ratio (ICER) of gene therapies. METHODS: A systematic review was conducted to include health economic evaluations of gene therapies that were published until April 2023. RESULTS: Sensitivity or scenario analysis indicated that discount rate represented one of the most influential factors for the ICERs of gene therapies. Discount rate for cost and benefit was positively correlated with the cost-effectiveness of gene therapies, that is, a lower discount rate significantly improves the ICERs. The alternative discount rate employed in some cases could be powerful to alter the conclusion on whether gene therapies are cost-effective and acceptable for reimbursement. CONCLUSIONS: Although discount rate will have substantial influence on the ICERs of gene therapies, there lacks solid evidence to justify a different discounting rule for gene therapies. However, it is proposed that the discount rate in the reference case should be updated to reflect the real-time preference, which in turn will affect the ICERs and reimbursement of gene therapies more profoundly than conventional therapies.

Methods for Indirect Treatment Comparison: Results from a Systematic Literature Review.

INTRODUCTION: Health technology assessment (HTA) agencies express a clear preference for randomized controlled trials when assessing the comparative efficacy of two or more treatments. However, an indirect treatment comparison (ITC) is often necessary where a direct comparison is unavailable or, in some cases, not possible. Numerous ITC techniques are described in the literature. A systematic literature review (SLR) was conducted to identify all the relevant literature on existing ITC techniques, provide a comprehensive description of each technique and evaluate their strengths and limitations from an HTA perspective in order to develop guidance on the most appropriate method to use in different scenarios. METHODS: Electronic database searches of Embase and PubMed, as well as grey literature searches, were conducted on 15 November 2021. Eligible articles were peer-reviewed papers that specifically described the methods used for different ITC techniques and were written in English. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 73 articles were included in the SLR, reporting on seven different ITC techniques. All reported techniques were forms of adjusted ITC. Network meta-analysis (NMA) was the most frequently described technique (in 79.5% of the included articles), followed by matching-adjusted indirect comparison (MAIC) (30.1%), network meta-regression (24.7%), the Bucher method (23.3%), simulated treatment comparison (STC) (21.9%), propensity score matching (4.1%) and inverse probability of treatment weighting (4.1%). The appropriate choice of ITC technique is critical and should be based on the feasibility of a connected network, the evidence of heterogeneity between and within studies, the overall number of relevant studies and the availability of individual patient-level data (IPD). MAIC and STC were found to be common techniques in the case of single-arm studies, which are increasingly being conducted in oncology and rare diseases, whilst the Bucher method and NMA provide suitable options where no IPD is available. CONCLUSION: ITCs can provide alternative evidence where direct comparative evidence may be missing. ITCs are currently considered by HTA agencies on a case-by-case basis; however, their acceptability remains low. Clearer international consensus and guidance on the methods to use for different ITC techniques is needed to improve the quality of ITCs submitted to HTA agencies. ITC techniques continue to evolve quickly, and more efficient techniques may become available in the future.

Cost-Effectiveness Analysis of Innovative Therapies for Patients with Non-Alcoholic Fatty Liver Disease.

OBJECTIVE: Currently there are no disease-specific approved therapies for non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); however, several treatments are under development. This study aimed to estimate the cost-effectiveness of hypothetical innovative therapies compared with lifestyle intervention alone and combined with pioglitazone, and assess the health economic consequences of their future availability for patients. METHODS: A Markov cohort model was developed, considering fourteen disease health states and one absorbing state representing death. Transition probabilities, costs, utilities, and treatment efficacy were based on published data and assumptions. Four treatment strategies were considered, including two existing therapies (lifestyle intervention, small molecule treatment) and two hypothetical interventions (biological and curative therapy). The analysis was performed from the US third-party payer perspective. RESULTS: The curative treatment with the assumed efficacy of 70% of patients cured and assumed price of $500,000 was the only cost-effective option. Although it incurred higher costs (a difference of $188,771 vs. lifestyle intervention and $197,702 vs. small molecule), it generated more QALYs (a difference of 1.58 and 1.38 QALYs, respectively), resulting in an ICER below the willingness-to-pay threshold of $150,000 per QALY. The sensitivity analyses showed that the results were robust to variations in model parameters. CONCLUSIONS: This study highlighted the potential benefits of therapies aimed at curing a disease rather than stopping its progression. Nonetheless, each of the analyzed therapies could be cost-effective compared with lifestyle intervention at a relatively high price.

Comprehensive evaluation of 45 augmentation drugs for schizophrenia: a network meta-analysis.

Background: Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network meta-analysis was to determine the efficacy of augmentation drugs for the treatment of schizophrenia. Methods: In accordance with the PRISMA statement, the PubMed, Web of Science, Google Scholar, CENTRAL, clinical trial and EUDRACT databases were searched from inception to May 15th, 2023. To ensure the robustness of the results, only double-blind randomised controlled trials with a low risk of bias (measured by the Risk Of Bias v2 (ROB2) tool) were included. The studies were categorised according to the background regimen: participants were treated with risperidone, mixed antipsychotics or clozapine. A Bayesian network meta-analysis was conducted using a random effects model. PROSPERO register: CRD42023420964. Findings: A total of 44 trials (comprising 45 augmentation drugs and 3358 participants) were included in the analysis. One-third of the drugs (16 drugs) demonstrated significant efficacy vs. placebo for at least one outcome. The most notable effect sizes (ESs) were observed for the use of tropisetron (standard mean difference: -0.83 [95% interval confidence -1.12 to -0.55]), memantine (-0.50 [-0.66 to -0.32]) and minocycline (-0.56 [-0.72 to -0.39]) to treat negative symptoms among patients treated with risperidone (moderate-to-high ESs). Studies involving mixed antipsychotics yielded lower ESs (small-to-moderate). Sodium benzoate (-0.41 [-0.60 to -0.21]) and memantine (-0.23 [-0.36 to -0.11]) were found have significant effects on positive symptoms, while memantine demonstrated efficacy for negative symptoms (-0.32 [-0.45 to -0.19]) and general psychopathology (-0.32 [-0.44 to -0.20]). Studies focusing exclusively on patients treated with clozapine revealed that duloxetine produced the best results (negative symptoms: -1.12 [-1.35 to -0.91]). Sodium benzoate was the only augmentation drug that demonstrated efficacy in relieving persistent positive symptoms (-0.32 [-0.59 to -0.08]) among patients treated with clozapine. Treatment with clozapine in combination with antipsychotics yielded small-to-moderate ESs. Interpretation: The GRADE framework indicated that the quality of the evidence among the included studies was moderate, primarily due to the limited number of randomised controlled trials with a low risk of bias. Important drugs did not appear in these results due to insufficient low-risk-of-bias data for these medications. These results highlight new pathways for treating schizophrenia that should be incorporated into future guidelines after further validation. Funding: No funding.

Drivers of patient and caregiver preferences for growth hormone deficiency treatments in France: a discrete choice experiment.

INTRODUCTION: To identify drivers of preference for growth hormone deficiency (GHD) treatment in French children, and their caregivers, and to quantify the relative importance of different aspects of treatment modalities using a discrete choice experiment (DCE). MATERIALS AND METHODS: Attributes characterizing GHD treatment modalities were identified through a literature review, qualitative interviews and focus groups with children, adolescents, and caregivers. A DCE questionnaire of 12 choice tasks was administered online to four groups of participants: autonomous adolescents (12 to 18 years), non-autonomous adolescent / caregiver dyads, caregivers of non-autonomous children (3 to 11 years) and autonomous children / caregiver dyads. The survey was pilot tested. A multinomial logit model with random effects was used to estimate preference weights for all attribute levels. RESULTS: Frequency of administration, injection pain, dose setting, type of device, storage and device reusability were selected as DCE attributes following the qualitative research phase and a pilot study. A total of 105 patients were represented in the DCE survey. Frequency of administration and injection pain were the attributes with the greatest influence on respondents' preferences and had similar importance. Weekly administration was significantly preferred over daily administration by all groups of participants. Respondents' choices were also significantly influenced by the type of device, dose setting and device reusability. CONCLUSION: Children with GHD and their caregivers prefer a less frequent injection schedule and lower injection pain. Both aspects of treatment modalities are important to consider in treatment decisions to alleviate the daily burden for GHD patients and their families and potentially enhance treatment adherence.

Recommendations for economic evaluations of cell and gene therapies: a systematic literature review with critical appraisal.

OBJECTIVE: No consensus exists on the ideal methodology to evaluate the economic impact and value of new, potentially curative gene therapies. We aimed to identify and describe published methodologic recommendations for the economic evaluation of gene therapies and assess whether these recommendations have been applied in published evaluations. METHODS: This study was conducted in three stages: a systematic literature review of methodologic recommendations for economic evaluation of gene therapies; an assessment of the appropriateness of recommendations; and a review to assess the degree to which the recommendations were applied in published evaluations. RESULTS: A total of 2,888 references were screened, 83 articles were reviewed to assess eligibility, and 20 papers were included. Fifty recommendations were identified, and 21 reached consensus thresholds. Most evaluations were based on naive treatment comparisons and did not apply consensus recommendations. Innovative payment mechanisms for gene therapies were rarely considered. The only widely applied recommendations related to modeling choices and methods. CONCLUSIONS: Methodological recommendations for economic evaluations of gene therapies are generally not being followed. Assessing the applicability and impact of the recommendations from this study may facilitate the implementation of consensus recommendations in future evaluations.

Valuation of Treatments for Rare Diseases: A Systematic Literature Review of Societal Preference Studies.

INTRODUCTION: We sought to synthesize published empirical studies that elicited and characterized societal valuations of orphan drugs and the attributes that may drive different valuations for orphan drugs versus other treatments. METHODS: We conducted a systematic literature review (SLR) in MEDLINE and EMBASE databases up to November 2, 2020. Search terms covered societal preferences and attributes of orphan drugs (e.g., disease prevalence, severity, burden, unmet needs, and benefits). RESULTS: We identified 38 eligible publications: 33 societal preference studies and 5 reviews discussing societal valuations and attributes of orphan drugs. Most publications suggested that a majority of respondents favored allocating funds to more prevalent diseases. However, trade-off studies and discrete-choice experiments found that survey participants chose to allocate resources to orphan drugs even when the cost per unit of health benefit was greater than for therapies for more prevalent diseases. Overall, 19 of 27 studies assessing severity in treatment valuation revealed that respondents prioritized patients with severe diseases over those with milder ones for equal health benefits. Members of the general public tended to prefer treatments for diseases with no alternative or when existing alternatives had limited efficacy over diseases with clear therapeutic alternatives. There was evidence that individuals preferred sharing resources, so no patient was left without treatment. CONCLUSIONS: Our SLR indicates the general public typically attaches greater value to orphan drugs than to other treatments for common diseases. This is not because of rarity per se, but primarily because of disease severity and lack of therapeutic alternatives typically associated with rare diseases.

Orphan drugs are drugs serving a substantial public health need by treating life-threatening or chronically debilitating medical conditions affecting a small number of people with very high unmet needs. We reviewed 38 published studies looking at drug characteristics that may cause people to value orphan drugs differently versus treatments for common conditions. Most people surveyed in these publications favored health care funds going to more prevalent diseases. However, some people preferred funding orphan drugs even when the cost versus health benefit was higher compared with treatments for more common diseases. The majority of studies that investigated the impact of disease severity on the valuation of treatments found that people prioritized patients with severe disease over those with milder disease, for the same extent of health benefit. People also preferred funding treatments for diseases that have no alternative treatments, or treatments with limited benefits, over treatments for diseases with many treatments or more effective treatments. We also found evidence of a societal preference for shared resources, meaning that no patient would be left without treatment, including those who receive limited benefits from health care resources, even if this does not lead to the maximization of health benefits across society. In conclusion, our literature review indicated that the general public attaches greater value to orphan drugs versus treatments for more common diseases, not because of rarity per se, but largely because the rare diseases treated by orphan drugs are often severe and have no or few treatment options.

Neurologists' preferences for device-aided therapy for advanced Parkinson's disease in Japan.

OBJECTIVE: This study measures the relative preference for attributes of device-aided therapies (DATs) for advanced Parkinson's Disease (PD) from the perspective of Japanese neurologists. METHODS: Attributes and levels were elicited based on literature and interviews with certified neurologists experienced with DATs. An online survey including a discrete choice experiment (DCE) was developed, pilot tested, and distributed through an online panel to neurologists treating advanced PD patients. Participants were asked to choose treatments among several choice sets of two hypothetical DATs described only by the attributes, or no DAT (continuing oral treatment). A conditional logit model using the Bayesian framework was developed to estimate the marginal utilities of attributes' levels, and the relative utility of treatments available to Japanese advanced PD patients or being developed in Japan was assessed. RESULTS: The DCE survey completed by 308 neurologists showed that the attributes with the greatest influence on DAT selection were surgery requirement (relative importance of 28%), average increase in the duration of daily "on" time without dyskinesia which affects daily activities (15%), average change in cognitive function related to treatment introduction (15%), device management frequency (14%), average number of pills of oral PD medication after treatment introduction (13%), average influence of treatment on symptoms of depression (12%), and type of device (large/small) (3%). All attributes significantly influenced respondents' choices, except for external device type. Experience with DATs did not influence the directions of preferences. Out of treatment profiles representing DATs, continuous subcutaneous infusion of levodopa-carbidopa had a higher preference score than levodopa-carbidopa intestinal gel infusion and deep brain stimulation. CONCLUSIONS: Our findings suggest that Japanese neurologists would prefer a DAT without surgery requirement. Other factors related to efficacy, safety, and administration mode have a significant, but a smaller influence on prescription choices.

Cost-effectiveness of recombinant factor VIII Fc versus emicizumab for prophylaxis in adults and adolescents with haemophilia A without inhibitors in the UK.

INTRODUCTION: The economic and clinical burden of haemophilia A is high. Primary prophylaxis with factor VIII replacement therapy is the recognised standard of care, but the emergence of non-factor therapies, such as emicizumab, is extending treatment options for people with haemophilia A. AIM: There are currently no direct comparisons of efficacy or cost between recombinant factor FVIII Fc-fusion protein efmoroctocog alfa (a recombinant factor FVIII Fc-fusion protein referred to herein as rFVIIIFc) and emicizumab; therefore, a cost-effectiveness model was developed to compare prophylactic treatment with rFVIIIFc versus emicizumab in patients with haemophilia A without inhibitors in the UK. METHODS: The cost-effectiveness model was based on a matching-adjusted indirect comparison and included male patients, aged ≥12 years, with haemophilia A without inhibitors. The model was designed as a Markov process with a flexible lifelong time horizon, and cost-effectiveness was presented as an incremental cost-effectiveness ratio. Base-case analysis and sensitivity analyses (including scenario analyses, one-way deterministic sensitivity analysis [DSA] and probability sensitivity analysis [PSA]) were performed using the following treatment strategies: individualised prophylaxis with rFVIIIFc and prophylaxis with emicizumab administered once weekly (scenario analyses used regimens of once every 2 weeks or once every 4 weeks). RESULTS: Base-case analysis, DSA and PSA indicated that, compared with emicizumab administered once weekly, rFVIIIFc individualised prophylaxis was the dominant treatment strategy, with lower costs, a greater number of quality-adjusted life years, and a lower number of bleeds. CONCLUSIONS: rFVIIIFc has proven efficacy and is cost-effective compared with emicizumab, providing clinicians with a viable treatment option to improve the health outcomes for adults and adolescents with haemophilia A in the UK.

Cost-minimization analysis of recombinant factor VIII Fc versus emicizumab for treating patients with hemophilia A without inhibitors in Europe.

BACKGROUND AND OBJECTIVE: A cost-minimization model was developed to compare recombinant factor VIII Fc (rFVIIIFc) and emicizumab as prophylaxis for hemophilia A without inhibitors. METHODS: The model was based on 100 patients from the healthcare payer perspective in the UK, France, Italy, Spain, and Germany (5-year time horizon). Costs included: drug acquisition; emicizumab wastage by bodyweight (manufacturer's dosing recommendations); and additional FVIII for breakthrough bleeds. Scenario analyses (UK only): reduced emicizumab dosing frequency; and emicizumab maximum wastage. RESULTS: Total incremental 5-year savings for rFVIIIFc rather than emicizumab use range from €89,320,131 to €149,990,408 in adolescents/adults (≥12 years) and €173,417,486 to €253,240,465 in children (<12 years). Emicizumab wastage accounts for 6% of its total cost in adolescents/adults and 26% in children. Reducing the emicizumab dosing frequency reduces the incremental cost savings with rFVIIIFc, but these remain substantial (adolescents/adults, >€92 million; children >€32 million). Maximum emicizumab wastage increases by 86% and 106%, respectively, increasing the incremental cost savings with rFVIIIFc to €125,352,125 and €105,872,727, respectively. CONCLUSION: Based on cost-minimization modeling, rFVIIIFc use for hemophilia A prophylaxis in patients without inhibitors is associated with substantial cost savings in Europe, reflecting not only higher acquisition costs of emicizumab, but also other costs including wastage related to available vial sizes.

Improvement in pain-related quality of life in patients with hemophilia A treated with rFVIIIFc individualized prophylaxis: post hoc analysis from the A-LONG study.

BACKGROUND: Pain, a common symptom of hemophilia, begins early in life primarily due to joint bleeding. Recurrent bleeding adversely affects patients' pain-related physical functioning, which can negatively impact their quality of life (QoL). OBJECTIVE: Post hoc analysis of data from the A-LONG study (NCT01181128), to assess change over time in pain-related QoL in patients with severe hemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein (rFVIIIFc). METHODS: Patients who completed Haem-A-QoL (17-65 years) and EQ-5D-3L (⩾12-65 years) questionnaires at baseline (BL) and end of study (EoS). Individual-level changes were assessed using three pain-related items of the Haem-A-QoL 'Physical Health' domain and the pain/discomfort item of EQ-5D-3L. Distributions of responses (EoS versus BL) were compared using McNemar's test. RESULTS: A significantly greater proportion of patients reported they did not experience painful swellings (n = 87; 66% versus 46%, p < 0.01) or pain in their joints (n = 89; 42% versus 27%; p < 0.05) at EoS versus BL. The proportion of patients who did not find it painful to move numerically increased at EoS versus BL (n = 86; 47% versus 38%; p = NS). A significantly greater proportion of patients reported no pain/discomfort at EoS versus BL (n = 116; 45% versus 34%; p < 0.05). CONCLUSION: This study reports the effect of FVIII prophylaxis on patient-reported measures of pain over time in patients with severe hemophilia A. The results of this post hoc analysis showed improvements in pain from BL to EoS in patients receiving rFVIIIFc individualized prophylaxis indicating effective pain management, a key component of patient care.

Challenges in the market access of regenerative medicines, and implications for manufacturers and decision-makers: a systematic review.

Aim: Regenerative medicines (RMs) are expected to transform the treatment paradigm of rare, life-threatening diseases, while substantial challenges impede its market access. This study aimed to present these challenges. Materials & methods: Publications identified in the Medline and Embase databases until December 2020 were included. Results: Uncertainties around the relative effectiveness and long-term benefits of RMs are most scrutinized. A new reference case for RMs is questionable, but examining impacts of study perspective, time horizon, discount rate and extrapolation methods on estimates is advised. Establishing reasonable prices of RMs requires increased transparency in the development costs and better values measurements. Outcome-based payments require considerable investments and potential legislative adjustments. Conclusion: Greater flexibility for health technology assessment and economic analyses of RMs is necessary. This comprehensive review may prompt more multi-stakeholder conversations to discuss the optimized strategy for value assessment, pricing and payment in order to accelerate the market access of RMs.

Plain language summary Regenerative medicines (RMs) potentially offered new hopes for severe diseases without effective treatments. However, substantial challenges must be overcome to make them available for patients. This systematic review aims to present these challenges. Publications identified in the Medline and Embase databases until December 2020 were included. The limited clinical evidence causes the biggest uncertainties around the relative effectiveness and long-term benefits of RMs. The current methodology for economic analysis of RMs is questionable because broader, societal values related to RMs are not sufficiently captured. The high price of RMs seems unjustified and should be lowered by balancing the development costs and values delivered. Outcome-based payments could be employed to address the long-term financial challenges, but they will require investments to implement it. More flexibility for health technology assessment and economic analysis of RMs is necessary to safeguard the accelerated patient access.

rFIXFc prophylaxis improves pain and levels of physical activity in haemophilia B: Post hoc analysis of B-LONG using haemophilia-specific quality of life questionnaires.

INTRODUCTION: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL). AIM: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity. METHODS: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL. RESULTS: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL. CONCLUSION: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc.

An overview of health technology assessments of gene therapies with the focus on cost-effectiveness models.

BACKGROUND: Gene therapies can treat, prevent, or cure a disease by changing the expression of a person's genes. They are an innovative strategy for treating genetic disorders; however, they are still emerging on the market access and in the healthcare system. Health technology assessment (HTA) agencies have not yet elaborated any standardised approach for assessing gene therapies; therefore, significant differences can be seen during HTAs carried out in various countries. In this review, we focused on submitted economic models of gene therapies approved for use by the US FDA and EMA with the aim to provide a comprehensive summary of how selected HTA bodies assessed the cost-effectiveness of gene therapies. An additional objective was to examine and discuss differences in the methods used in economic models across countries and drugs. METHODS: We identified economic models of gene therapies from six countries (NICE, IQWiG, SMC, HAS, CADTH, ICER) and focused on nine agents (Glybera, Imlygic, Strimvelis, Yescarta, Kymriah, Luxturna, Zynteglo, Zolgensma, Tecartus). Details of cost-utility evaluations and budget impact models were reviewed and extracted. RESULTS: Overall, 983 publications were identified, and 17 studies were included for the analysis. Reviewed evaluations of gene therapies differed in terms of the study perspective, discounting, extrapolation of outcomes based on limited and immature data, time horizon, and adequate estimation of benefits in terms of quality-adjusted life-years. Methods of economic evaluations were in line with the current recommendations; however, long-term follow-up studies are still missing. CONCLUSIONS: Discrepancies in an economic evaluation of gene therapies between different HTA bodies are rooted in a lack of general assessment frameworks specific to gene therapies. Although challenges were resolved by adjustments to the currently used value assessment framework, new methodological approaches would be useful. In addition, to improve the methods and quality of an evaluation, further research would be valuable.

On the association between SARS-COV-2 variants and COVID-19 mortality during the second wave of the pandemic in Europe.

OBJECTIVE: This study aims at investigating associations between COVID-19 mortality and SARS-COV-2 variants spread during the second wave of COVID-19 pandemic in Europe. METHODS: For 38 European countries, data on numbers of COVID-19 deaths, SARS-COV-2 variants spread through time using Nextstrain classification, demographic and health characteristics were collected. Cumulative number of COVID-19 deaths and height of COVID-19 daily deaths peak during the second wave of the pandemic were considered as outcomes. Pearson correlations and multivariate generalized linear models with selection algorithms were used. RESULTS: The average proportion of B.1.1.7 variant was found to be a significant predictor of cumulative COVID-19 deaths within two months before the peak and between 1 January-25 February 2021, as well as of the deaths peak height considering proportions during the second wave and the pre-peak period. The average proportion of EU2 variant (S:477 N) was a significant predictor of cumulative COVID-19 deaths in the pre-peak period. CONCLUSIONS: Our findings suggest that spread of a new variant of concern B.1.1.7 had a significant impact on mortality during the second wave of COVID-19 pandemic in Europe and that proportions of EU2 and B.1.1.7 variants were associated with increased mortality in the initial phase of that wave.

How pet owners choose antiparasitic treatments for their dogs: A discrete choice experiment.

BACKGROUND: External and internal parasites can cause significant pathology to pets, posing distress to their owners. Antiparasitic treatment is complex because there are many antiparasitic products and dog owners have a limited understanding of parasiticides. The aim of this study was to investigate the characteristics of antiparasitic treatments available at veterinary offices to help veterinarians understand what pet owners value when selecting parasiticides for their dogs. METHODS: Discrete choice experiment (DCE) methodology was used. A list of important treatment attributes was developed based on semi-structured interviews with six dog owners with a total of nine dogs and six veterinarians. The questionnaire including 12 choices between pairs of hypothetical products defined according to treatment attributes was developed. The questionnaire was administered to UK dog owners recruited through an internet panel. It was tested in a pilot study with 17 dog owners, and then was completed by 160 dog owners in the main study. RESULTS: The selected treatment attributes were price, spectrum of action, veterinarian recommendation, treatment schedule, mode of administration, and place of obtention. The main analysis showed the first four of these attributes significantly influenced the preferences of dog owners for antiparasitic treatments. The most important factor was spectrum of action; most owners expressed a preference for products treating multiple parasites. The influence of price was comparable to that of spectrum of action. Pet owners were more likely to choose a product recommended by their veterinarian. Willingness-to-pay estimates were £11.22 [€12.68; $15.38] for extending protection from fleas and ticks only to intestinal worm and lungworm and £7.21 [€8.14; $9.87] for recommendation from veterinarian. CONCLUSIONS: A broad spectrum of action, veterinarian recommendation, and price are key drivers for choosing antiparasitic products among dog owners. These results may help veterinarians with recommendations of antiparasitic treatment for pet owners based on the key drivers pet owners value.

The real-life impact of vaccination on COVID-19 mortality in Europe and Israel.

OBJECTIVES: This study aimed at estimating the real-life impact of vaccination on COVID-19 mortality, with adjustment for SARS-CoV-2 variants spread and other factors across Europe and Israel. STUDY DESIGN: Time series analysis. METHODS: Time series analysis of the daily number of COVID-19 deaths was performed using non-linear Poisson mixed regression models. Variables such as variants' frequency, demographics, climate, health, and mobility characteristics of thirty-two countries between January 2020 and April 2021 were considered as potentially relevant adjustment factors. RESULTS: The analysis revealed that vaccination efficacy in terms of protection against deaths was 72%, with a lower reduction of the number of deaths for B.1.1.7 vs non-B.1.1.7 variants (70% and 78%, respectively). Other factors significantly related to mortality were arrivals at airports, mobility change from the prepandemic level, and temperature. CONCLUSIONS: Our study confirms a strong effectiveness of COVID-19 vaccination based on real-life public data, although lower than expected from clinical trials. This suggests the absence of indirect protection for non-vaccinated individuals. Results also show that vaccination effectiveness against mortality associated with the B.1.1.7 variant is slightly lower than that with other variants. Lastly, this analysis confirms the role of mobility reduction, within and between countries, as an effective way to reduce COVID-19 mortality and suggests the possibility of seasonal variations in COVID-19 incidence.

Considering potential solutions for limitations and challenges in the health economic evaluation of gene therapies.

INTRODUCTION: The limited evidence in the clinical trials of gene therapies (GTs) posed substantial challenges for a reliable health technology assessment (HTA). This paper provides insights into the relationship between the background of diseases and the health economics assessment of GTs.Areas covered: The impacts of differentiated severity and unmet needs of genetic diseases, on the economic analysis of GTs, were discussed.Expert opinion: GTs offer a potential cure or significant clinical improvement, while limitations in clinical evidence constitute major obstacles for a robust assessment of clinical effectiveness and economic outcomes. This uncertainty may be balanced by the severity of the targeted condition and the associated unmet needs, thus leading to a relatively higher acceptance for GTs. Overtime, HTA agencies will become more demanding on comprehensive evidence of long-term effectiveness. With a growing number of GTs on the horizon, to what extent the unmet needs of previously devastating diseases will be fulfilled remain unclear. Nonetheless, comparative studies, either with a historical control group or existing treatments, will be necessary to demonstrate the additional benefits associated with GTs.

Efficacy of rFIXFc versus rIX-FP for the Treatment of Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PROLONG-9FP Trials.

PURPOSE: In patients with hemophilia B, treatment with extended half-life (EHL) recombinant factor IX allows for longer dosing intervals while providing equal or superior bleeding protection compared with standard half-life products. This enables flexible, individualized treatment schedules, which reduce the burden of prophylaxis and improve patient outcomes. This analysis compared the efficacy of recombinant factor IX Fc fusion protein (rFIXFc) and recombinant factor IX albumin fusion protein (rIX-FP), two EHL therapies approved for prophylaxis and treatment of bleeding in hemophilia B. PATIENTS AND METHODS: Matching-adjusted indirect treatment comparison (MAIC) was used to adjust the between-treatment differences in baseline characteristics. Individual patient data for rFIXFc (B-LONG) were matched to aggregated data for rIX-FP (PROLONG-9FP) followed by statistical comparison for estimated annualized bleeding rate (ABR) using a Poisson regression model with adjustment for over dispersion. Data were analyzed according to treatment regimen prior to study entry: prior prophylaxis (rFIXFc, n=48; rIX-FP, n=40) or prior episodic treatment (n=43 and n=19, respectively). Relative treatment effects are presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). RESULTS: After adjustment for baseline characteristics, estimated ABR observed for rFIXFc and rIX-FP was not significantly different in patients on prior prophylaxis (1.87 versus 1.58; IRR 1.18, 95% CI 0.67-2.10) or prior episodic (2.25 versus 2.22; IRR 1.01 95% CI 0.40-2.57) regimens. CONCLUSION: This MAIC analysis shows that the estimated ABR for rFIXFc-treated patients from B-LONG was similar to that of rIX-FP-treated patients from PROLONG-9FP and, therefore, indicates that the two EHL therapies provide similar efficacy when used as prophylaxis for patients with hemophilia B. Trough levels differ between the two products (1-3% [targeted] versus 20% [observed], respectively), suggesting that trough level is not a surrogate indicator when ABR is used as a criterion for clinical efficacy when comparing these FIX products in hemophilia B.

Cost-effectiveness of baloxavir marboxil compared with laninamivir for the treatment of influenza in patients at high risk for complications in Japan.

OBJECTIVE: Baloxavir marboxil (baloxavir) is a single-dose antiviral which was previously found to be a cost-effective alternative to laninamivir in otherwise healthy adults in Japan. This study aimed at investigating the cost-effectiveness of baloxavir versus laninamivir in patients with influenza at high risk for complications. METHODS: A decision tree was utilized to estimate costs and health gains associated with the use of antivirals. A lifetime horizon was applied to capture the long-term impact of influenza complications, and other events with associated costs and health outcomes were accounted for one influenza season. The study population was stratified into three categories: adolescents and non-elderly adults with high-risk conditions (HRC), elderly without other HRC, and elderly with other HRC. The cost-effectiveness was assessed from a public healthcare payer's perspective. The duration of influenza symptoms, probabilities of complications and probabilities of adverse events were obtained from a clinical trial and network meta-analysis. The costs of influenza and adverse events management were derived from the JammNet claims database. Utility values were informed by the clinical trial data and literature. Sensitivity analyses were also performed. RESULTS: The baloxavir strategy was associated with higher costs (+¥144) and higher quality-adjusted life-years (QALYs) in adults with HRC, elderly without HRC and elderly with HRC (+0.00078, +0.00183 and +0.00350 respectively). The overall incremental cost/QALY for baloxavir versus laninamivir was ¥68,855, which was below the willingness-to-pay threshold of ¥5 million/QALY gained. Key drivers of the model results were the probability of pneumonia and bronchitis. The probability of baloxavir being cost-effective was 72%. CONCLUSIONS: This study suggests that influenza treatment with baloxavir is cost-effective compared with laninamivir in the adult high-risk population in Japan.