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Introduction: The value of gene therapies for haemophilia needs to be assessed holistically., Aim: To determine the value of etranacogene dezaparvovec (ED) compared to current extended half-life (EHL) recombinant factors (rFIX), using multi-criteria decision analysis (MCDA)., Method: MCDA EVIDEM methodology adapted to orphan drugs was used, with nine quantitative criteria and four contextual criteria. The MCDA framework was rated by 28 multidisciplinary experts. Descriptive statistics were performed for quantitative and qualitative criteria., Results: Haemophilia B (HB) was considered a severe disease (mean ± SD: 4.3 ± 0.7) with some unmet needs (mean ± SD 3.3 ± 0.9). Experts found ED more effective (mean ± SD 2.0 ± 2.3) and provide better quality of life (QoL) (mean ± SD: 1.8 ± 1.5) than the comparative HB treatments but with safety uncertainties (mean ± SD -1.2 ± 1.8). ED could lead to medical cost and non-medical cost savings over time (mean ± SD: 1.6 ± 2.0 and 2.0 ± 1.5, respectively). The quality of the evidence was high (mean ± SD: 3.9 ± 0.9). ED was considered aligned with the priorities of the National Health System (NHS) and the specific interests of patients. ED's value contribution was 0.45 (+1 = highest value)., Conclusions: ED brings added value in the treatment of moderately severe and severe HB (sHB) compared to current EHL rFIX, addressing the severity of the disease and increasing efficacy and patients' QoL especially related to the single dose and low bleeding rate. Concerns about long-term safety need to be addressed., (© 2024 John Wiley & Sons Ltd.)

Background: The aim of this study was to assess the contribution of the reflective multidisciplinary discussion in determining the value contribution of innovative drugs through the multi-criteria decision analysis (MCDA). This methodology considers all relevant criteria for healthcare decision-making in a global, transparent, and systematic manner and from the perspective of relevant stakeholders. The determination of value contribution of tabelecleucel for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV + PTLD) compared to salvage therapy was used as an example., Results: Tabelecleucel obtained a value contribution score of 0.63 and increased to 0.75 after the reflective discussion. EBV + PTLD was considered a life-threatening disease (5.0 ± 0.0), with a significant unmet need for an approved treatment (5.0 ± 0.0). Tabelecleucel was perceived as bringing improvements in terms of efficacy (4.2 ± 0.8) and safety (3.8 ± 0.8) compared to the salvage therapy. Most experts considered that the high efficacy and safety results could represent an improvement in the quality of life of patients (2.3 ± 1.2) along with savings in medical costs (2.3 ± 2.0) and non-medical costs (2.7 ± 1.6) compared to the salvage therapy. However, others emphasized the need of more evidence to confirm these improvements and savings over time. Tabelecleucel was regarded as potentially modifying the clinical course of the disease (4.3 ± 0.8) and supported by high-quality evidence (3.2 ± 0.4). All contextual criteria were valued highly positively for tabelecleucel. "Safety/Tolerability" and "Other medical costs" were the criteria that experienced the highest change in the re-test conducted after the reflective discussion. The reflective discussion allowed resolving doubts or misinterpretations of the experts, so the re-test obtained more accurate and consistent results of the value contribution of tabelecleucel., Conclusions: The study shows that the MCDA methodology is a useful tool for decision-making on innovative treatments for the management of rare diseases. It also highlights the importance of reflective multidisciplinary discussion for its ability to resolve doubts or misinterpretations of experts, subsequently allowing to obtain more consistent and reliable results on the value contribution of the drug, being potentially more positive., (© 2024. The Author(s).)

Introduction: High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity., Methods: A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population., Results: Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts' hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21-40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU., Conclusions: These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.

Introduction: Carbapenem-resistant Gram-negative bacteria (CRGN) are an urgent public health threat because of the limited treatment options, its rapid spreading and high clinical impact and mortality rates. However, the burden and the use of resources of these infections have not been investigated. The aim of the current study is to understand the use of resources associated to the clinical management of CRGN infections in real clinical practice conditions., Methods: An observational retrospective chart review study was performed. Data regarding patient demographics, clinical management and use of resources associated to hospitalization were retrieved from clinical charts of ICU inpatients with a confirmed CRGN infection. Three reference Spanish hospitals were selected according to their patient volume and geographical coverage. Descriptive analyses of the clinical management and the use of resources and its cost were performed and then total costs by type of resource were calculated., Results: A total of 130 patients were included in the study. The higher number of patients (n=43; 33%) were between 61 and 70 years old. Ninety-four (72%) patients were male and 115 (88%) suffered from comorbidities. The mean total cost associated to the resources used in patients with CRGN infections hospitalized in ICU was 96,878€ per patient. These total costs included 84,140€ of total hospital stay, 11,021€ of treatments (558€ of antibiotics; 10,463€ of other treatments) and 1717€ costs of diagnostic tests., Conclusions: CRGN infection causes a high use of hospital resources, being the length of stay either in hospital wards or ICU the driver of the total costs. Diagnostic tests and treatments, including antibiotics, represent the lowest part of the use of resources and costs (13% of total costs)., (Copyright © 2021 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Background: The present study aims to assess clinical and regulatory variables that would influence pricing and reimbursement (P&R) decisions for Orphan Drugs (ODs) in Spain. ODs approved by the European Commission (EC) between 2006 and 2021 were classified according to their P&R status in Spain: approved, undergoing decision and rejected. A statistical analysis was carried out to assess the potential association between clinical and regulatory variables and P&R decision of ODs in Spain: therapeutic area, rarity of disease, existence of alternative therapies, availability of survival-related outcomes, safety profile, type of population, conditional approval status granted by the European Medicines Agency (EMA) and a positive Therapeutic Positioning Report (TPR) opinion., Results: 111 ODs have been approved by the EC and have obtained marketing authorisation in Spain between 2006 and 2021. Out of the 111 ODs, 57 (51.4%) were reimbursed, 24 (21.6%) were undergoing decision and 30 (27%) were rejected. According to the statistical analysis, ODs with a positive TPR conclusion (p-value < 0.01), not subject to a conditional approval by the EMA (p-value < 0.05) and approved without the obligation to conduct a post-authorisation safety study (PASS) (p-value < 0.05), were statistically significant, and therefore, would be more likely to obtain P&R approval in Spain., Conclusions: This study shows that the TPR plays a key role in the P&R process in Spain and highlights that traditional evaluation tools, such us safety and efficacy, were the main drivers of P&R decisions for ODs. A positive conclusion of the TPR, non-conditional approval by the EMA and no obligation for a PASS seems to favourably affect P&R decisions in Spain., (© 2023. The Author(s).)

Objective: Risk factors (RFs) associated with infection progression in patients already colonised by carbapenem-resistant Gram-negative bacteria (CRGNB) have been addressed in few and disperse works. The aim of this study is to identify the relevant RFs associated to infection progression in patients with respiratory tract or rectal colonisation., Methods: A systematic literature review was developed to identify RFs associated with infection progression in patients with CRGNB respiratory tract or rectal colonisation. Identified RFs were then evaluated and discussed by the expert panel to identify those that are relevant according to the evidence and expert's experience., Results: A total of 8 articles were included for the CRGNB respiratory tract colonisation and 21 for CRGNB rectal colonisation, identifying 19 RFs associated with pneumonia development and 44 RFs associated with infection progression, respectively. After discussion, the experts agreed on 13 RFs to be associated with pneumonia development after respiratory tract CRGNB colonisation and 33 RFs to be associated with infection progression after rectal CRGNB colonisation. Respiratory tract and rectal colonisation, previous stay in the ICU and longer stay in the ICU were classified as relevant RF independently of the pathogen and site of colonisation. Previous exposure to antibiotic therapy or previous carbapenem use were also common relevant RF for patients with CRGNB respiratory tract and rectal colonisation., Conclusions: The results of this study may contribute to the early identification of CRGNB colonized patients at higher risk of infection development, favouring time-to-effective therapy and improving health outcomes., (©The Author 2022. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

A hydrocoele surgery facility assessment tool (HSFAT) was developed to assess the readiness of hydrocoele surgery services in health facilities prior to implementation of hydrocoele surgical campaigns for the elimination of lymphatic filariasis (LF). A first version of the tool was piloted in Bangladesh, Malawi and Nepal in 2019, then, following feedback from country programme managers, a second version of the tool was rolled out across countries implementing hydrocoele surgery in the Accelerating the Control of Neglected Tropical Diseases (Ascend) West and Central Africa Programme, including Benin, Burkina Faso, Ghana, Guinea, Niger and Nigeria. The HSFAT assessed facilities across 10 domains: background information, essential amenities, emergency patient transfer, laboratory capacity, surgical procedures and trained staff, infection prevention, non-disposable basic equipment, disposable basic equipment, essential medicines and current hydrocoele practices. The HSFAT results highlight key areas for improvement in different countries and can be used to develop a quality improvement plan, which may include actions with agreed deadlines to improve the readiness and quality of hydrocoele surgery services provided by the health facility, prior to implementation of surgical campaigns and assist country programmes to achieve the dossier requirements set out by the World Health Organization for the elimination of LF., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Objective: To determine the value contribution of cabotegravir + rilpivirine, the first injectable every two months long-acting antiretroviral  regimen, using multi-criteria decision analysis., Method: The study was developed in two phases. After a small pilot, a field  ork study with a larger number of multidisciplinary experts was carried out.  Seven single-tablet regimens, currently recommended by the GeSIDA  guidelines, were selected as comparators. EVIDEM methodology was followed,  with a framework composed by 12 quantitative and 5 contextual criteria. Mean  and standard deviations were calculated for quantitative criteria (1 to 5 scale;  comparative criteria -5 to +5), whereas qualitative criteria were analyzed as  percentages of experts that considered a positive, neutral or negative impact  for the National Health System., Results: 35 experts participated in the study. Human immunodeficiency virus- 1 infection was considered severe (mean ± standard deviation: 3.0 ± 1.0),  with moderate size of affected population (2.7 ± 1.2) and unmet needs (2.8 ±  1.0). Minimal differences were found in comparative efficacy/effectiveness (0.1  ± 0.5), safety/tolerability (-0.5 ± 0.7), and cost criteria: cost of the  intervention (0.5 ± 2.0), other medical costs (0.2 ± 1.8) and non- medical/indirect costs (0.5 ± 1.6). Experts perceived an improvement with  cabotegravir + rilpivirine long-acting, compared  to current daily oral single-tablet regimens, in patient-reported outcomes (2.7 ± 1.4). Therapeutic benefit  of the long-acting regimen was considered moderate-to-high (3.5 ± 1.2).  Experts considered the evidence provided by cabotegravir + rilpivirine long- actingrobust (4.3 ± 0.8), with elevated consensus on its future  recommendation in guidelines (3.2 ± 1.0). In contextual criteria, most experts  considered positive the impact on population priorities and access (91%),  common goal and specific interests (63%) and political, historical, and cultural  context criteria (60%). Impact was neutral in system capacity and appropriate  use (40%), and opportunity costs and affordability criteria (51%). Result of the  weighted global value contribution of cabotegravir + rilpivirine long-acting  was 0.34 (-1 to +1 scale), with Patient Reported Outcomes comparative  criterion bringing the highest added value., Conclusions: Cabotegravir + rilpivirine long-acting provides added value  contribution to human immunodeficiency virus-1 management in Spain  compared to daily oral single-tablet regimens. Patient Reported Outcomes and  therapeutic benefit of cabotegravir + rilpivirine long-acting were highly valued  by experts, as the expected benefit in adherence and stigma-related issues  would improve overall quality of life for people living with human  immunodeficiency virus-1., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Objectives: The reimbursement of medicines by the Spanish National Health System (NHS) is based on a set of criteria included in the Royal Legislative Decree 1/2015 (RDL 1/2015). The Interministerial Committee on Pricing of Medicines and Healthcare Products (CIPM) is responsible for the final price and reimbursement (P&R) decision, including on its resolutions the criteria listed in the law by which the reimbursement of a drug is approved or denied. Nevertheless, the information behind its reasoning is not provided. The present study aims to characterize the P&R criteria of the RDL 1/2015 through criteria definitions from other countries to improve the P&R evaluation in Spain., Results: A multidisciplinary experts panel with relevant experience in drug evaluation and decision making at national, regional, and local level in Spain was selected for this study. A literature review to characterize the criteria listed in the RDL 1/2015 was performed based on the most relevant and recognized Health Technology Assessment (HTA) agencies in Europe, UK, and Canada. Eventually, a feasibility study was performed to evaluate the novel drug cefiderocol using the characterized criteria, including a reflective discussion of the results., Conclusions: Consensus was reached among the multidisciplinary experts on the characterization of the criteria set by the law. The feasibility of their application to a new drug was exploratory, notwithstanding it showed the potential to improve the transparency as well as to offer a more structured rationale for the CIPM to evaluate the inclusion of new drugs in the Spanish NHS.