Use of hospital resources in ICU inpatients with infections caused by carbapenem-resistant Gram-negative bacteria: A real clinical practice-based study in Spain / Uso de recursos hospitalarios en pacientes hospitalizados en UCI debido a infecciones causadas por bacterias gramnegativas resistentes a carbapenémicos: un estudio basado en la práctica clínica real en España

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).(AU)

Introducción: Las bacterias gramnegativas resistentes a carbapenémicos (CRGN) son una amenaza urgente de salud pública por las limitadas opciones de tratamiento, su rápida dispersión y el alto impacto clínico y tasas de mortalidad. Sin embargo, la carga y el uso de recursos de estas infecciones no han sido investigadas. El objetivo de este estudio es comprender el uso de recursos asociado al manejo clínico de las infecciones por CRGN en condiciones de práctica clínica real. Métodos: Se llevó a cabo un estudio observacional retrospectivo de revisión de historias clínicas. Se recogieron datos demográficos, del manejo clínico y del uso de recursos asociado a la hospitalización de historias clínicas de pacientes hospitalizados en UCI con una infección confirmada por CRGN. Se seleccionaron tres hospitales españoles de referencia por su cobertura geográfica. Se realizaron análisis descriptivos del manejo clínico y el uso de recursos y sus costes en episodios de infecciones por CRGN, y se calcularon los costes totales para cada tipo de recurso. Resultados: Se incluyeron en el estudio un total de 130 pacientes. La mayoría de los pacientes (n=43;33%) tenían entre 61-70 años. Noventa y cuatro pacientes (72%) eran hombres y 115 (88%) presentaron comorbilidades. El coste medio total asociado a los recursos usados durante el episodio de infección por CRGN por paciente fue de 96.878€. Este coste total incluye 84.140€ de la estancia en el hospital, 11.021€ de los tratamientos (558€ de antibióticos y 10.463€ de otros tratamientos) y 1.717€ del coste de test diagnósticos. Conclusiones: El episodio de infección por CRGN causa un alto uso de recursos hospitalarios, siendo la duración de la estancia tanto en planta hospitalaria como en UCI el factor con mayor peso de los costes totales. Los test diagnósticos clínicos y los tratamientos, incluyendo los antibióticos, representan la parte más pequeña del uso de recursos y sus costes (13% del coste total).(AU)

ODs with a positive TPR conclusion, not subject to a conditional approval, and approved without requering a pass would be more likely to be reimbursed in Spain.

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.

Use of hospital resources in ICU inpatients with infections caused by carbapenem-resistant Gram-negative bacteria: A real clinical practice-based study in Spain.

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).

Incidence and management of patients with methotrexate delayed elimination in the clinical practice: A Delphi study.

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.

Contribution of cabotegravir + rilpivirine long-acting for the treatment of HIV-1 infection.

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.

OBJETIVO: Determinar la contribución de valor de cabotegravir + rilpivirina, el  primer tratamiento antirretroviral inyectable de acción prolongada, utilizando  metodología de análisis de decisión multicriterio.Método: El estudio se desarrolló en dos fases: una prueba piloto y una fase de  extensión, con un grupo multidisciplinar más grande. Se seleccionaron siete regímenes de comprimido único orales diarios  recomendados en las guías GeSIDA como comparadores. Se utilizó el marco  EVIDEM, compuesto por 12 criterios cuantitativos y 5 contextuales. Los  criterios cuantitativos se analizaron calculando la media y desviación estándar,  y los cualitativos se analizaron mediante el porcentaje de expertos que  consideraron el impacto positivo, neutro o negativo para el Sistema Nacional de Salud. RESULTADOS: Un total de 35 expertos participaron en el estudio. La infección  por virus de la inmunodeficiencia humana 1 se consideró grave (media ±  desviación estándar: 3,0 ± 1,0), con un tamaño de población afectada (2,7 ±  1,2) y unas necesidades no cubiertas (2,8 ± 1,0) moderadas. Las diferencias  fueron mínimas en los criterios comparativos de eficacia/efectividad (0,1 ±  0,5), seguridad/tolerabilidad (­0,5 ± 0,7) y coste: coste del tratamiento (0,5 ±  2,0), otros costes médicos (0,2 ± 1,8) y costes no-médicos/indirectos (0,5  ± 1,6). Los expertos observaron una emtrimejora con cabotegravir + rilpivirina  de acción prolongada en los resultados reportados por los pacientes  (2,7 ± 1,4). El beneficio terapéutico (3,5 ± 1,2) se consideró moderado-alto.  La evidencia de cabotegravir + rilpivirina de acción prolongada fue considerada  robusta (4,3 ± 0,8), con elevado consenso sobre su futura  recomendación en las guías (3,2 ± 1,0). En los criterios contextuales, el  impacto fue positivo en los criterios de prioridades de acceso (91%), objetivo  común (63%) y contexto político (60%). El impacto fue neutro en la capacidad  del sistema (40%) y los costes de oportunidad (51%). El resultado  promedio de la contribución del valor global de cabotegravir + rilpivirina de  acción prolongada fue de 0,34 (escala de ­1 a +1), siendo el criterio de  resultados reportados por el paciente el que proporcionó la mayor contribución de valor (0,04). CONCLUSIONES: Cabotegravir + rilpivirina de acción prolongada aporta un valor  añadido en el manejo del virus de la inmunodeficiencia humana 1 en  España en comparación con los regímenes de comprimido único utilizados  actualmente. Los expertos valoraron positivamente los resultados reportados  por los pacientes y el beneficio terapéutico de cabotegravir + rilpivirina de  acción prolongada, considerando que el beneficio esperado en la adherencia y  los problemas relacionados con el estigma produciría una mejora en la calidad  de vida de las personas con virus de la inmunodeficiencia humana 1.

The development and roll-out of a new hydrocoele surgery facility assessment tool for the elimination of lymphatic filariasis.

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.

Feasibility study to characterize price and reimbursement decision-making criteria for the inclusion of new drugs in the Spanish National Health System: the cefiderocol example.

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.

Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain / Determinación de la carga de las infecciones causadas por bacterias gramnegativas resistentes a carbapenemas en España

Objective: To estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. Methods: The burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. Results: Approximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. Conclusion: CRGN nosocomial infections have a high clinical impact on patients’ lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.(AU)

Objetivo: Estimar la carga de las infecciones nosocomiales inducidas por patógenos gramnegativos resistentes a carbapenemas (GNRC) en España, focalizada tanto en el impacto clínico como en el económico. Métodos: La carga de la enfermedad se estimó utilizando datos del año 2017, de acuerdo con la disponibilidad de los mismos en bases de datos. Se analizó el impacto, tanto clínico como económico, de las infecciones nosocomiales GNRC más habituales (causadas por Klebsiella pneumoniae, Pseudomonas aeruginosa y Acinetobacter baumannii). Se estimaron la incidencia y la mortalidad de las infecciones nosocomiales GNRC, así como los costes directos e indirectos derivados de este problema de salud. Resultados: Aproximadamente 376.346 pacientes podrían haber sufrido una infección nosocomial en España durante el año 2017; siendo el 3,2% de ellas producidas por bacilos GNRC. Las infecciones causadas por P. aeruginosa resistente a carbapenemas produjeron las mayores tasas de mortalidad (2.578 muertes) en comparación con A. baumannii (1.571) y K. pneumoniae (415). Los costes económicos totales de las infecciones nosocomiales producidas por GNRC en España se estimaron en 472 M€ en 2017, siendo el 83% del coste total representado por los costes directos. Conclusión: Las infecciones nosocomiales producidas por GNRC tienen un gran impacto en la vida de los pacientes, altas tasas de mortalidad y representan uno de los episodios de hospitalización con más costes hospitalarios asociados. Se deben focalizar los esfuerzos en políticas de prevención para evitar las infecciones por patógenos GNRC y su carga, así como para reducir los costes directos producidos por la morbimortalidad, concretamente en aquellas infecciones producidas por P. aeruginosa.(AU)

Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain.

OBJECTIVE: To estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. METHODS: The burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. RESULTS: Approximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. CONCLUSION: CRGN nosocomial infections have a high clinical impact on patients' lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.

Impact of the therapeutic positioning report in the P&R process in Spain: analysis of orphan drugs approved by the European Commission and reimbursed in Spain from 2003 to 2019.

BACKGROUND: Pricing and reimbursement decisions for orphan drugs are faced with differences access between European countries depending on each reimbursement policies, evaluation processes and timings. In 2013, the therapeutic positioning report was introduced in the pricing and reimbursement process in Spain. The present study aims to identify orphan drugs authorised in Spain and approved by the European Commission between January 2003 and December 2019, analyse the impact of the therapeutic positioning report in the pricing and reimbursement process of orphan drugs in Spain and to assess additional potential criteria that could influence pricing and reimbursement decisions for orphan drugs. RESULTS: Ninety-four orphan drugs have been approved by the European Commission between January 2003 and December 2019 and have marketing authorisation in Spain. Out of the 94 orphan drugs, 46 (48.9%) had received pricing and reimbursement approval. Before the inclusion of the therapeutic positioning report in year 2013, the mean time from European Commission approval to pricing and reimbursement approval for orphan drugs in Spain was 25.1 ± 16.5. After 2013, timelines have been reduced by an average of 9 months. The mean regulatory time from European Commission approval to Spanish marketing authorisation has decreased nearly 4 months (from 7.5 ± 10.2 months in years 2003-2013 to 3.8 ± 7.6 months in years 2014-2019). The instauration of the therapeutic positioning report could be associated with a reduction of the mean time from the Spanish marketing authorisation to pricing and reimbursement approval by an average of 5 months (from 17.3 ± 13.1 months in years 2003-2013 to 12.3 ± 5 months in years 2014-2019). In addition, orphan drugs with a positive conclusion in the therapeutic positioning report would be more likely to be reimbursed in Spain (p < 0,0001). CONCLUSIONS: This study shows that the therapeutic positioning report plays a key role in the pricing and reimbursement process in Spain. A positive conclusion of the therapeutic positioning report seems to favourably affect pricing and reimbursement decisions in Spain and, since its introduction, has also contributed to reduce pricing and reimbursement approval timelines in Spain.

Development of a Multicriteria Decision Analysis Framework for Evaluating and Positioning Oncologic Treatments in Clinical Practice.

PURPOSE: Several frameworks have been developed to define and quantify the value of oncologic therapies and to support decision making; however, they define treatment value mainly in terms of clinical benefit. As part of its mission to improve oncologic care, the ECO Foundation (Excellence and Quality in Oncology) directed this pilot study aimed at developing a reflective multicriteria decision analysis (MCDA)-based framework for evaluating and positioning oncologic drugs in the clinical setting. METHODS: The framework was developed following Evidence and Value: Impact on Decision-Making methodology, and literature was reviewed to identify relevant criteria. The selected criteria were then presented to a group of experts composed of 9 clinical oncologists who assessed each criterion for inclusion in the framework and suggested modifications in their definition and/or response scale. The framework was tested in 2 case studies (abemaciclib for advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer and TAS-102 for metastatic colorectal cancer) to validate the proposed framework; this was followed by a discussion of the results. RESULTS: Eight of the 15 criteria presented to the experts were included in the framework: disease severity, unmet needs, comparative efficacy, comparative safety/tolerability, treatment intent, comparative treatment cost, comparative other medical costs, and quality of evidence. Framework validation in 2 drug cases resulted in similar value scores, although they were based on different contributing criteria and resulted in different clinical recommendations. CONCLUSION: We developed and validated a reflective MCDA framework for the assessment and positioning of oncologic therapies in Spain. Additional work is needed to create a manual for practical decision making in the clinical setting.

Analysing criteria for price and reimbursement of orphan drugs in Spain / Análisis de los criterios sobre precio y financiación de los medicamentos huérfanos en España

Objective: There are differences between countries regarding data requirements for orphan drug evaluation and it is also unknown which criteria might determine the price and reimbursement decision. This study aimed to identify the key criteria for price and reimbursement of orphan drugs in Spain, approved by the European Commission, between January 2012 and June 2018. Method: A descriptive analysis of the orphan drugs and its characteristics was performed. Outcomes criteria assessed were: therapeutic area, existence of alternative treatment, rarity of the disease, clinical trial outcomes and therapeutic positioning report assessment. Hypotheses for each variable regarding Spanish pricing and reimbursement were made and tested with two regression analyses. Results: Out of 78 orphan drugs approved by the European Commission, 82.1% asked pricing and reimbursement in Spain. From this, 43.8% had pricing and reimbursement approved and 20.3% rejected. Mean time from Spanish marketing authorisation approval to pricing and reimbursement approval was 12.1 ± 5.1 months. Having a positive therapeutic positioning report and no therapeutic alternatives would be associated with a positive pricing and reimbursement in Spain. Conclusions: It remains challenging to establish which are the driving criteria for pricing and reimbursement approval of orphan drugs in Spain. Further research should be done including other variables that might influence the pricing and reimbursement final decision in Spain

Objetivo: Los requisitos para la evaluación de los medicamentos huérfanos difieren entre los países miembros de la Unión Europea y tampoco se sabe qué criterios influyen en la decisión final sobre precio y financiación. Este estudio ha tenido como objetivo identificar los criterios clave para establecer el precio y la financiación de los medicamentos huérfanos en España, una vez aprobados por la Comisión Europea, entre enero de 2012 hasta junio de 2018. Método: Se realizó un análisis descriptivo de los medicamentos huérfanos y sus características. Los criterios evaluados fueron: área terapéutica, existencia de tratamientos alternativos, rareza de la enfermedad, tipo de resultados de los ensayos clínicos e informe de posicionamiento terapéutico. Para cada variable se estableció una hipótesis con respecto a la aprobación de precio y financiación y se analizaron con dos análisis de regresión. Resultados: De las 78 aprobaciones de medicamentos huérfanos realizadas por la Comisión Europea, el 82,1% solicitaron precio y financiación en España. De estas, el 43,8% fueron aprobadas y el 20,3% fueron rechazadas. El tiempo medio desde la aprobación de la autorización de comercialización en España hasta la aprobación del precio y la financiación fue de 12,1 ± 5,1 meses. Un informe de posicionamiento positivo y la falta de alternativas terapéuticas se asociaría con una aprobación de precio y financiación. Conclusiones: Sigue siendo un reto establecer cuáles son los criterios clave para la aprobación de los medicamentos huérfanos en España. Los próximos estudios deberían incluir un mayor número de variables que puedan influir en el precio y la decisión de financiación

Analysing criteria for price and reimbursement of orphan drugs in Spain.

OBJECTIVE: There are differences between countries regarding data requirements for orphan drug evaluation and it  is also unknown which criteria might determine the price and reimbursement decision. This study aimed to identify the key  criteria for price and reimbursement of orphan drugs in Spain, approved by the European Commission, between January 2012 and June 2018. METHOD: A descriptive analysis of the orphan drugs and its characteristics was performed. Outcomes criteria assessed  were: therapeutic area, existence of alternative treatment, rarity of the disease, clinical trial outcomes and therapeutic  positioning report assessment. Hypotheses for each variable regarding Spanish pricing and reimbursement were made  and tested with two regression analyses. RESULTS: Out of 78 orphan drugs approved by the European Commission, 82.1% asked pricing and reimbursement in  Spain. From this, 43.8% had pricing and reimbursement approved and 20.3% rejected. Mean time from Spanish  marketing authorisation approval to pricing and reimbursement approval was 12.1 ± 5.1 months. Having a positive  therapeutic positioning report and no therapeutic alternatives would be associated with a positive pricing and  reimbursement in Spain. CONCLUSIONS: It remains challenging to establish which are the driving criteria for pricing and reimbursement approval  of orphan drugs in Spain. Further research should be done including other variables that might influence the pricing and  reimbursement final decision in Spain.

Objetivo: Los requisitos para la evaluación de los medicamentos huérfanos difieren entre los países  miembros de la Unión Europea y tampoco se sabe qué criterios influyen en la decisión final sobre  precio y financiación. Este estudio ha tenido como objetivo identificar los criterios clave para establecer el precio y la financiación de los medicamentos huérfanos en España, una vez  aprobados por la Comisión Europea, entre enero de 2012 hasta junio de 2018.Método: Se realizó un análisis descriptivo de los medicamentos huérfanos y sus características. Los  criterios evaluados fueron: área terapéutica, existencia de tratamientos alternativos, rareza de la  enfermedad, tipo de resultados de los ensayos clínicos e informe de posicionamiento terapéutico. Para  cada variable se estableció una hipótesis con respecto a la aprobación de precio y  financiación y se analizaron con dos análisis de regresión.Resultados: De las 78 aprobaciones de medicamentos huérfanos realizadas por la Comisión Europea,  el 82,1% solicitaron precio y financiación en España. De estas, el 43,8% fueron aprobadas  y el 20,3% fueron rechazadas. El tiempo medio desde la aprobación de la autorización de comercialización en España hasta la aprobación del precio y la financiación fue de 12,1 ± 5,1  meses. Un informe de posicionamiento positivo y la falta de alternativas terapéuticas se asociaría con  una aprobación de precio y financiación.Conclusiones: Sigue siendo un reto establecer cuáles son los criterios clave para la aprobación de los  medicamentos huérfanos en España. Los próximos estudios deberían incluir un mayor número de  variables que puedan influir en el precio y la decisión de financiación.

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut).

BACKGROUND: Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. METHODS: The assessment and decision-making process for orphan drugs in the Programa d'Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. RESULTS: The final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria "disease severity", "unmet need", "comparative effectiveness" and "comparative safety /tolerability". The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. CONCLUSIONS: The study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access.

Patient involvement in reflective multicriteria decision analysis to assist decision making in oncology.

OBJECTIVES: Patient involvement in drug evaluation decision making is increasing. The aim of the current study was to develop a multi-criteria decision analysis (MCDA) framework that would enable the inclusion of the patient perspective in the selection of appropriate criteria for MCDAs being used in the value assessments of oncologic drugs. METHODS: A literature review was conducted to identify and define criteria used in drug assessments from patient perspectives. The Evidence and Value: Impact on Decision Making methodology was used to develop a MCDA framework. Identified criteria were discussed by a sample of oncology patient association representatives who decided which criteria were important from patient perspectives. Selected criteria were rated by importance. The preliminary MCDA framework was tested through the assessment of a hypothetical oncology treatment. A discussion was carried out to agree on a final pilot MCDA framework. RESULTS: Twenty-two criteria were extracted from the literature review. After criteria discussion, sixteen criteria remained. The most important criteria were comparative patient reported outcomes (PRO), comparative efficacy and disease severity. After the discussion generated by the scoring of the hypothetical oncology treatment, the final pilot MCDA framework included seven quantitative criteria ("disease severity", "unmet needs", "comparative efficacy / effectiveness", "comparative safety / tolerability", "comparative PROs", "contribution of oncological innovation") and one contextual criterion ("population priorities and access"). CONCLUSIONS: The present study developed a pilot reflective MCDA framework that could increase patient's capability to participate in the decision-making process by providing systematic drug assessments from the patient perspective.

MULTI-CRITERIA DECISION ANALYSIS AS A DECISION-SUPPORT TOOL FOR DRUG EVALUATION: A PILOT STUDY IN A PHARMACY AND THERAPEUTICS COMMITTEE SETTING.

OBJECTIVES: The aim of this study was to develop and to assess a specific Multi-Criteria Decision Analysis (MCDA) framework to evaluate new drugs in an hospital pharmacy and therapeutics committee (P&TC) setting. METHODS: A pilot criteria framework was developed based on the EVIDEM (Evidence and Value: Impact on DEcisionMaking) framework, together with other relevant criteria, and assessed by a group of P&TC's members. The weighting of included criteria was done using a 5-point weighting technique. Two drugs were chosen by evaluation: an orphan-drug for Gaucher disease, and a nonorphan drug for the treatment of inflammatory bowel disease. Evidence matrices were developed, and value contribution of each drug was evaluated by P&TC's members. An agreed final framework was obtained through a discussion between the P&TC's members. RESULTS: After criteria assessment, the pilot framework included eight quantitative criteria: "disease severity," "unmet needs," "comparative efficacy/effectiveness," "comparative safety/tolerability," "comparative patient-reported outcomes," "comparative cost consequences-cost of treatment," "comparative cost consequences-other medical costs," and "quality of evidence"; and one contextual criterion: "opportunity costs and affordability." The most valued criteria were: "comparative safety/tolerability," "disease severity," and "comparative efficacy/effectiveness." When assessing the drugs most valued characteristics of the MCDA were the possibility that all team may contribute to drug assessment by means of scoring the matrices and the discussion to reach a consensus in drug positioning and value decision making. CONCLUSIONS: The reflective MCDA would integrate quantitative and qualitative criteria relevant for a P&TC setting, allowing reflective discussions based on the criteria weighting score.

Patient-centered assessment on disease burden, quality of life, and treatment satisfaction associated with acromegaly.

The study aimed to assess the economic burden, health-related quality of life (HRQoL), and acromegaly treatment satisfaction in the USA. A web-based, cross-sectional survey was distributed to members of Acromegaly Community. Data related to comorbidities, treatment patterns, and treatment satisfaction were collected. The costs over the past 3 months included out-of-pocket cost, sick leave, leave of absence, direct loss of job due to acromegaly, unemployment, assistance to perform household chores, and family member loss of income. The HRQoL was assessed by Acromegaly Quality of Life (AcroQoL) and EQ-5D-3L questionnaires. Among 106 patients who completed the survey (mean age: 46 years, female: 76.4%), 44.3% presented with ≥5 comorbidities, and 90.6% reporting acromegaly-related symptoms. Compared with the low-symptom group 0-3 (n=41), the 4+ symptoms group (n=65) was more likely to have depression (OR=2.3, 95% CI 1.1 to 5.2) and cardiovascular disease (OR=5.8, 95% CI 2.0 to 16.7), and experienced higher costs (loss of job: $8874 vs $1717, P=0.02; unemployment disability: $17,102 vs $429, P=0.003; household chores: $2160 vs $932, P=0.0003; family members' income loss: $692 vs $122, P=0.03). The high-symptom group had lower HRQoL scores, compared with the low-symptom group (EQ-5D-3L: 0.53 vs 0.75, P<0.0001; AcroQoL: 27 vs 56, P<0.0001). Only 55.7% among patients requiring injections for acromegaly were satisfied. Patients with acromegaly who presented with multiple acromegaly-related symptoms were evidenced to have experienced higher economic burden and poorer quality of life than patients with the same diagnosis but fewer symptoms. The low rate of treatment satisfaction warrants need for further studies.

Mapping AcroQoL scores to EQ-5D to obtain utility values for patients with acromegaly.

AIMS: To estimate a preference-based single index for the disease-specific instrument (AcroQoL) by mapping it onto the EQ-5D to assist in future economic evaluations. MATERIALS AND METHODS: A sample of 245 acromegaly patients with AcroQoL and EQ-5D scores was obtained from three previously published European studies. The sample was split into two: one sub-sample to construct the model (algorithm construction sample, n = 184), and the other one to confirm it (validation sample, n = 61). Various multiple regression models including two-part model, tobit model, and generalized additive models were tested and/or evaluated for predictive ability, consistency of estimated coefficients, normality of prediction errors, and simplicity. RESULTS: Across these studies, mean age was 50-60 years and the proportion of males was 36-59%. At overall level the percentage of patients with controlled disease was 37.4%. Mean (SD) scores for AcroQoL Global Score and EQ-5D utility were 62.3 (18.5) and 0.71 (0.28), respectively. The best model for predicting EQ-5D was a generalized regression model that included the Physical Dimension summary score and categories from questions 9 and 14 as independent variables (Adj. R2 = 0.56, with mean absolute error of 0.0128 in the confirmatory sample). Observed and predicted utilities were strongly correlated (Spearman r = 0.73, p < .001) and paired t-Student test revealed non-significant differences between means (p > .05). Estimated utility scores showed a minimum error of ≤10% in 45% of patients; however, error increased in patients with an observed utility score under 0.2. The model's predictive ability was confirmed in the validation cohort. LIMITATIONS AND CONCLUSIONS: A mapping algorithm was developed for mapping of AcroQoL to EQ-5D, using patient level data from three previously published studies, and including validation in the confirmatory sub-sample. Mean (SD) utilities index in this study population was estimated as 0.71 (0.28). Additional research may be needed to test this mapping algorithm in other acromegaly populations.

Development of ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly.

PURPOSE: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. METHODS: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. RESULTS: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. CONCLUSION: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.

DRUG EVALUATION AND DECISION MAKING IN CATALONIA: DEVELOPMENT AND VALIDATION OF A METHODOLOGICAL FRAMEWORK BASED ON MULTI-CRITERIA DECISION ANALYSIS (MCDA) FOR ORPHAN DRUGS.

OBJECTIVES: The aim of this study was to adapt and assess the value of a Multi-Criteria Decision Analysis (MCDA) framework (EVIDEM) for the evaluation of Orphan drugs in Catalonia (Catalan Health Service). METHODS: The standard evaluation and decision-making procedures of CatSalut were compared with the EVIDEM methodology and contents. The EVIDEM framework was adapted to the Catalan context, focusing on the evaluation of Orphan drugs (PASFTAC program), during a Workshop with sixteen PASFTAC members. The criteria weighting was done using two different techniques (nonhierarchical and hierarchical). Reliability was assessed by re-test. RESULTS: The EVIDEM framework and methodology was found useful and feasible for Orphan drugs evaluation and decision making in Catalonia. All the criteria considered for the development of the CatSalut Technical Reports and decision making were considered in the framework. Nevertheless, the framework could improve the reporting of some of these criteria (i.e., "unmet needs" or "nonmedical costs"). Some Contextual criteria were removed (i.e., "Mandate and scope of healthcare system", "Environmental impact") or adapted ("population priorities and access") for CatSalut purposes. Independently of the weighting technique considered, the most important evaluation criteria identified for orphan drugs were: "disease severity", "unmet needs" and "comparative effectiveness", while the "size of the population" had the lowest relevance for decision making. Test-retest analysis showed weight consistency among techniques, supporting reliability overtime. CONCLUSIONS: MCDA (EVIDEM framework) could be a useful tool to complement the current evaluation methods of CatSalut, contributing to standardization and pragmatism, providing a method to tackle ethical dilemmas and facilitating discussions related to decision making.