Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer: A systematic review and assessment of subgroup analyses.

BACKGROUND: Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer presents considerable controversy. There is literature suggesting lack of benefit for low-volume of metastases. OBJECTIVE: The study aims to develop a systematic review and methodological assessment of subset analysis about use of docetaxel in metastatic hormone-sensitive prostate cancer regarding volume of metastatic disease. METHODS: A systematic review in the Pubmed® database was conducted up to 25 September 2020. A reference tracking was also developed. Randomised clinical trials with subgroup analysis according volume of metastatic disease for overall survival were selected. Two methodologies were used. One of them considered statistical interaction of subsets (p(i) < 0.1), pre-specification, biological plausibility and consistency among subset results of similar randomised clinical trials. The second methodology was a two-part validated tool: preliminary questions to discard subset analysis without minimal relevance and a checklist The checklist provides recommendations for applicability of subgroup analysis in clinical practice. RESULTS: A total of 31 results were found in systematic reviews in the Pubmed® database. One result was identified in the reference tracking. Of the total of 32 results, four randomised clinical trials were included in the study. About first methodology, statistical interaction among subgroups was obtained in one randomised clinical trial. Subgroup analysis was pre-specified in two randomised clinical trials. Biological plausibility was reasonable. No external consistency among results of subgroup analyses in randomised clinical trials was observed. Preliminary questions of second methodology rejected applicability of subgroup analysis in three randomised clinical trials. A 'null' recommendation for applicability of subset results was obtained in the remaining randomised clinical trial. CONCLUSIONS: Patients with low- and high-burden metastatic hormone-sensitive prostate cancer would benefit from docetaxel therapy. No consistent differences for overall survival were observed in subgroup analyses regarding volume of metastatic disease.

Checklist for clinical applicability of subgroup analysis.

WHAT IS KNOWN AND OBJECTIVE: Subgroup analysis plays an important role in clinical decision-making. Correct management of subgroup analysis is necessary to optimize effectiveness, safety and efficiency of treatments. No homogeneous criteria have been developed for interpretation of subgroup analysis. In this study, the researcher develops a checklist to evaluate the reliability and applicability of the results of subset analyses. METHODS: With a review of previous literature, three main criteria were included in the checklist: statistical association, biological plausibility and consistency among studies. Statistical association considered interaction probability, prespecification of analysis, number of subgroups analysed, sample size and positive/negative result in global analysis. Each item was given an indicative score. Total score was related to a level of applicability for the results in clinical practice. Checklist validation included interinvestigator concordance and assessment about utility. Three drug examples were used to validate the tool. RESULTS AND DISCUSSION: Twenty-six evaluators showed adequate interinvestigator concordance (kappa 0.79, 1 and 0.83 for each drug example regarding applicability). Kappa values increased to 0.94, 1 and 1 after group discussion. Checklist utility score was greater than 4.7/5 in three drug examples. In pre-analysis, inter-researcher agreement on global applicability recommendation of subgroup results to practice was 92.3% (ramucirumab), 96% (nivolumab) and 100% (mepolizumab). In post-analysis, inter-researcher agreement on applicability recommendation of subgroup results was 100%, 94.45% and 100%, respectively. The checklist validation shows a high interindividual agreement of the results, both with respect to the evaluation of the applicability of subgroup analysis and concerning clinical decision-making. WHAT IS NEW AND CONCLUSION: We have developed the first validated tool for interpretation of subgroup analyses. The checklist contributes to the adoption of homogeneous criteria for subgroup analyses, thereby allowing discussion and evaluation of the effects of a health intervention.

Remdesivir and mortality reduction in COVID-19 patients: a systematized subgroup analysis of clinical trials.

OBJECTIVE: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non­high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets rom randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. METHOD: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis atached to SOLIDARITY study. It is structured in preliminary questions to  reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size,  number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of  similar studies. A score was assigned to each criterion and the tool related  global summation to a recommendation on the applicability of subset  results in clinical decision making. RESULTS: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained "null" assessment (-3 points), including a "doubtful" p of interaction (p = 0.0650) among  subgroups and mortality reached no statistical significance for global  population. These findings reduced the reliability of subset analysis.  Biological plausibility was considered "probable" (+3 points) because  antiviral could have a greater effect before the inflammatory process and  clinical worsening. Consistency between results of similar studies was  evaluated as "possible" (+2 points) analysis for compatibility of ACTT-1  and SOLIDARITY study results. The recommendation about application of  subset analysis results according to the risk of patients was "null". CONCLUSIONS: This structured interpretation of subgroup analysis  suggested too much uncertainty in hypothesis about remdesivir could  reduce mortality in patients with severe COVID-19 who required non-high- flow oxygen. It was probably a random finding. Therefore, a randomized  clinical trial about effect of remdesivir in mortality in patients with  COVID­19 and non-high-flow oxygen is essential.

Objetivo: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por  subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno ­no de alto flujo­. La difusión de  resultados del estudio SOLIDARITY se acompañó de un metaanálisis que  combinó resultados de mortalidad por subgrupos de los ensayos clínicos  aleatorizados. El objetivo del presente estudio es analizar  metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por  subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con  COVID-19.Método: Se usó una herramienta validada para valorar los hallazgos de  los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el  metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por  subgrupos sin condiciones mínimas relevantes, y un cuestionario  específico. Este último considera determinados criterios: asociación  estadística, incluyendo p de interacción, preespecificación de subgrupos,  tamaño muestral, número de factores valorados y resultado global del  estudio; plausibilidad biológica de las diferencias observadas; y  consistencia entre resultados de estudios similares. Se asignó una  puntuación a cada criterio y la herramienta relacionó el sumatorio global  con una recomendación sobre la aplicabilidad de los resultados de los  subgrupos en la toma de decisiones clínicas.Resultados: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo  valoración "nula" (­3 puntos), con p de interacción dudosa (p = 0,0650) y  resultado de mortalidad no significativo en población global, restando  fiabilidad al análisis de subgrupos. La plausibilidad biológica fue  considerada "probable" (+3 puntos), ya que el antiviral pudiera tener  mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La  consistencia se valoró "posible" (+2 puntos) por compatibilidad de  resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de  aplicación del análisis por subgrupos según el riesgo de los pacientes fue  "nula".Conclusiones: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la  mortalidad en pacientes con COVID-19 grave que precisan oxígeno ­no de  alto flujo­ presenta demasiada incertidumbre, y es probable que sea un  hallazgo casual. Por tanto, es imprescindible la realización de un ensayo  clínico aleatorizado sobre mortalidad en pacientes con oxígeno ­no de alto  flujo­.

Economic evaluation and budgetary burden of mepolizumab in severe refractory eosinophilic asthma.

OBJECTIVE: Mepolizumab is indicated as an additional treatment of severe refractory eosinophilic asthma. The observed differences in  population subgroups according to plasma eosinophil count, the  existence of patients with high levels of immunoglobulin E who are  candidates of omalizumab and mepolizumab, as well as mepolizumab's  economic impact, lead to make efficient economic studies for clinical  decision making. The aim was to analyze mepolizumab's cost-efficacy  and budget impact. METHOD: Cost comparison and the use of mepolizumab's budgetary  impact was performed, from the Spanish National Health System's  perspective. Among the assessed alternatives, inhaled systemic  corticosteroids, plus long acting beta agonist (ß2) and/or oral systemic  corticosteroids in patients with non immunoglobulin E-mediated severe  allergic asthma, and said treatment along with omalizumab in patients  with immunoglobulin E mediated eosinophilic allergic asthma were  included. Its efficacy was evaluated through avoided clinically relevant  exacerbations. The direct costs associated with exacerbation were  assessed. RESULTS: Mepolizumab's long run average incremental cost regarding omalizumab's is 797 euros per patient a year. Considering  omalizumab's alternative discounted price, including mepolizumab for  patients with immunoglobulin E mediated eosinophilic allergic asthma  would increase public spending from 2.3 to 4.6 million euros. Given  omalizumab's notified price, the gradual introduction of mepolizumab in  the Spanish National Health System would save 3.6 million euros in  three years. For non immunoglobulin E-mediated severe asthma  patients, the avoided cost/exacerbation by introducing mepolizumab is  15,085 euros, assuming a gradual market penetration of mepolizumab. In patients with ≥ 500 eosinophils/µL, this cost decreases to 7,767  euros per avoided exacerbation with a budgetary impact of 183.2 million  euros in three years with a progressive penetration of mepolizumab. CONCLUSIONS: The cost comparison between mepolizumab and  omalizumab in immunoglobulin E mediated eosinophilic asthma patients  suggests a use of the lower cost drug, promoting price competition.  Additionally, prioritizing its use among non immunoglobulin E-mediated  severe refractory eosinophilic asthma patients and ≥ 500 eosinophils/µL  plasma level patients, would improve its efficiency as well as  reducing its budgetary impact.

Objetivo: Mepolizumab está indicado como tratamiento adicional del asma eosinofílica refractaria grave. Las diferencias observadas en  subgrupos poblacionales según recuento eosinofílico plasmático,  existencia de pacientes con altos niveles de inmunoglobulina E  candidatos a omalizumab y mepolizumab, e impacto económico de  mepolizumab obligan a realizar estudios económicos para tomar  decisiones clínicas eficientes. El objetivo fue realizar un análisis de  coste/eficacia e impacto presupuestario de mepolizumab.Método: Se realizó la comparación de costes e impacto presupuestario del uso de mepolizumab desde la perspectiva del  Sistema Nacional de Salud. Las alternativas valoradas fueron  corticosteroides sistémicos inhalados + agonista ß2 de larga duración  y/o corticosteroides sistémicos orales en pacientes con asma alérgica  grave no mediada por inmunoglobulina E, y este tratamiento junto a  omalizumab en pacientes con asma eosinofílica alérgica mediada por  inmunoglobulina E. La eficacia se evaluó mediante exacerbaciones  clínicamente relevantes evitadas. Se valoraron los costes directos  asociados a exacerbación.Resultados: El coste incremental medio de mepolizumab respecto a omalizumab es de 797 euros por paciente y año. Considerando precio alternativo con descuento de omalizumab, incluir mepolizumab  para pacientes con asma eosinofílica alérgica y mediada por  inmunoglobulina E supondría incrementar el gasto público de 2,3 a 4,6  millones de euros. Teniendo en cuenta el precio notificado de  omalizumab, la introducción gradual de mepolizumab en el Sistema  Nacional de Salud supondría ahorrar 3,6 millones de euros en tres años.  Para pacientes con asma grave no mediada por inmunoglobulina  E, el coste/exacerbación evitada al añadir mepolizumab es de 15.085  euros, con un impacto presupuestario en tres años de 578,4 millones de  euros, asumiendo una penetración progresiva de mepolizumab en el  mercado. En los pacientes con ≥ 500 eosinófilos/µl, este coste  disminuye a 7.767 euros por exacerbación evitada, con un impacto  presupuestario de 183,2 millones de euros en tres años con penetración  progresiva de mepolizumab.Conclusiones: La comparación de costes entre mepolizumab y  omalizumab en pacientes con asma eosinofílica mediada por  inmunoglobulina E señala como razonable utilizar el fármaco de menor  coste, promoviendo competencia de precios. Asimismo, priorizar su uso  en pacientes con asma eosinofílica refractaria grave no mediada por  inmunoglobulina E y niveles plasmáticos ≥ 500 eosinófilos/µl permitiría  mejorar la eficiencia y disminuir el impacto presupuestario.

Evaluación económica y análisis de impacto presupuestario de mepolizumab en asma eosinofílica refractaria grave / Economic evaluation and budgetary burden of mepolizumab in severe refractory eosinophilic asthma

Objetivo: Mepolizumab está indicado como tratamiento adicional del asma eosinofílica refractaria grave. Las diferencias observadas en subgrupos poblacionales según recuento eosinofílico plasmático, existencia de pacientes con altos niveles de inmunoglobulina E candidatos a omalizumab y mepolizumab, e impacto económico de mepolizumab obligan a realizar estudios económicos para tomar decisiones clínicas eficientes. El objetivo fue realizar un análisis de coste/eficacia e impacto presupuestario de mepolizumab. Método: Se realizó la comparación de costes e impacto presupuestario del uso de mepolizumab desde la perspectiva del Sistema Nacional de Salud. Las alternativas valoradas fueron corticosteroides sistémicos inhalados + agonista ß2 de larga duración y/o corticosteroides sistémicos orales en pacientes con asma alérgica grave no mediada por inmunoglobulina E, y este tratamiento junto a omalizumab en pacientes con asma eosinofílica alérgica mediada por inmunoglobulina E. La eficacia se evaluó mediante exacerbaciones clínicamente relevantes evitadas. Se valoraron los costes directos asociados a exacerbación. Resultados: El coste incremental medio de mepolizumab respecto a omalizumab es de 797 euros por paciente y año. Considerando precio alternativo con descuento de omalizumab, incluir mepolizumab para pacientes con asma eosinofílica alérgica y mediada por inmunoglobulina E supondría incrementar el gasto público de 2,3 a 4,6 millones de euros. Teniendo en cuenta el precio notificado de omalizumab, la introducción gradual de mepolizumab en el Sistema Nacional de Salud supondría ahorrar 3,6 millones de euros en tres años. Para pacientes con asma grave no mediada por inmunoglobulina E, el coste/exacerbación evitada al añadir mepolizumab es de 15.085 euros, con un impacto presupuestario en tres años de 578,4 millones de euros, asumiendo una penetración progresiva de mepolizumab en el mercado. En los pacientes con ≥ 500 eosinófilos/µl, este coste disminuye a 7.767 euros por exacerbación evitada, con un impacto presupuestario de 183,2 millones de euros en tres años con penetración progresiva de mepolizumab. Conclusiones: La comparación de costes entre mepolizumab y omalizumab en pacientes con asma eosinofílica mediada por inmunoglobulina E señala como razonable utilizar el fármaco de menor coste, promoviendo competencia de precios. Asimismo, priorizar su uso en pacientes con asma eosinofílica refractaria grave no mediada por inmunoglobulina E y niveles plasmáticos ≥ 500 eosinófilos/µl permitiría mejorar la eficiencia y disminuir el impacto presupuestario

Objective: Mepolizumab is indicated as additional treatment of severe refractory eosinophilic asthma. Differences in subgroups according to plasmatic eosinophil count, existence of patients with high levels of immunoglobulin E candidates for omalizumab and mepolizumab, and budget impact of mepolizumab require economic studies for efficient clinical decisions. The objective was to perform a cost-efficacy and budget impact analysis of mepolizumab. Method: An analysis of comparison of costs and budgetary impact of use of mepolizumab has been performed from National Health System perspective. Evaluated alternatives were inhaled systemic corticosteroids + long-acting ß2-agonist and/or oral systemic corticosteroids in patients with severe allergic asthma not mediated by immunoglobulin E, and the same treatment associated with omalizumab in patients with immunoglobulin E-mediated allergic eosinophilic asthma. Efficacy was assessed by clinically relevant exacerbations avoided. Direct costs associated with exacerbation were assessed Results: An average incremental cost of 797 euros/patient-year was estimated. Considering alternative price with discount for omalizumab, including mepolizumab for patients with immunoglobulin E-mediated allergic eosinophilic asthma would increase public spending from 2.3 to 4.6 million euros. According reported price for omalizumab, gradual introduction of mepolizumab into the National Health System would save 3.6 million euros in three years. For patients with immunoglobulin E-not mediated severe asthma, adding mepolizumab presented a cost/exacerbation avoided of 15,085 euros and a budgetary impact for three years of 578.4 million euros according a progressive penetration of mepolizumab in market. In patients with ≥ 500 eosinophils/μL, cost/exacerbation avoided is reduced to 7,767 euros and the budgetary impact is 183.2 million euros in three years according progressive penetration of mepolizumab. Conclusions: With analysis of cost comparison of mepolizumab vs. omalizumab in patients with eosinophilic immunoglobulin E-mediated asthma, it would be reasonable to prioritize the drug more economic to promote price competition. According this pharmacoeconomic study, prioritizing mepolizumab in patients with immunoglobulin E-not mediated severe refractory eosinophilic asthma and higher plasmatic eosinophil count (≥ 500 eosinophils/μL) would improve efficiency and decrease budgetary impact

Remdesivir y reducción de mortalidad en pacientes con COVID-19: análisis sistematizado de subgrupos de los ensayos clínicos / Remdesivir and mortality reduction in COVID-19 patients: a systematized subgroup analysis of clinical trials

OBJETIVO: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno -no de alto flujo-. La difusión de resultados del estudio SOLIDARITY se acompañó de un metaanálisis que combinó resultados de mortalidad por subgrupos de los ensayos clínicos aleatorizados. El objetivo del presente estudio es analizar metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con COVID-19. MÉTODO: Se usó una herramienta validada para valorar los hallazgos de los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por subgrupos sin condiciones mínimas relevantes, y un cuestionario específico. Este último considera determinados criterios: asociación estadística, incluyendo p de interacción, preespecificación de subgrupos, tamaño muestral, número de factores valorados y resultado global del estudio; plausibilidad biológica de las diferencias observadas; y consistencia entre resultados de estudios similares. Se asignó una puntuación a cada criterio y la herramienta relacionó el sumatorio global con una recomendación sobre la aplicabilidad de los resultados de los subgrupos en la toma de decisiones clínicas. RESULTADOS: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo valoración "nula" (-3 puntos), con p de interacción dudosa (p = 0,0650) y resultado de mortalidad no significativo en población global, restando fiabilidad al análisis de subgrupos. La plausibilidad biológica fue considerada "probable" (+3 puntos), ya que el antiviral pudiera tener mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La consistencia se valoró "posible" (+2 puntos) por compatibilidad de resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de aplicación del análisis por subgrupos según el riesgo de los pacientes fue "nula". CONCLUSIONES: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la mortalidad en pacientes con COVID-19 grave que precisan oxígeno -no de alto flujo- presenta demasiada incertidumbre, y es probable que sea un hallazgo casual. Por tanto, es imprescindible la realización de un ensayo clínico aleatorizado sobre mortalidad en pacientes con oxígeno -no de alto flujo-

OBJECTIVE: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non-high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets from randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. METHOD: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis attached to SOLIDARITY study. It is structured in preliminary questions to reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size, number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of similar studies. A score was assigned to each criterion and the tool related global summation to a recommendation on the applicability of subset results in clinical decision making. RESULTS: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained "null" assessment (-3 points), including a "doubtful" p of interaction (p = 0.0650) among subgroups and mortality reached no statistical significance for global population. These findings reduced the reliability of subset analysis. Biological plausibility was considered "probable" (+3 points) because antiviral could have a greater effect before the inflammatory process and clinical worsening. Consistency between results of similar studies was evaluated as "possible" (+2 points) analysis for compatibility of ACTT-1 and SOLIDARITY study results. The recommendation about application of subset analysis results according to the risk of patients was "null". CONCLUSIONS: This structured interpretation of subgroup analysis suggested too much uncertainty in hypothesis about remdesivir could reduce mortality in patients with severe COVID-19 who required non-high-flow oxygen. It was probably a random finding. Therefore, a randomized clinical trial about effect of remdesivir in mortality in patients with COVID-19 and non-high-flow oxygen is essential