The relevance of therapeutic positioning in the post-approval evaluation of new medicines. / La importancia del posicionamiento terapéutico en la evaluación posautorización de nuevos medicamentos.

The objective of regulatory authorities is to ensure a favorable risk-benefit balance for medicines in their licensed indication, without seeking to establish their place in the therapeutic armamentarium beyond that. The licensed indication covers heterogeneous subpopulations and often does not sufficiently specify the characteristics of the patients who may benefit. The regulatory information does not always show the benefit over the standard treatments; moreover, it only reacts to the conditions specified in the developer's application, and lacks an assessment of the clinical relevance of the benefit and its uncertainties. Many cases highlight the need to establish a more specific therapeutic benefit scenario than the licensed indication. For example, abemaciclib was approved in the adjuvant setting for high-risk patients with early breast cancer, but the appropriate level of risk and how to assess it needs to be specified. Also, pembrolizumab is approved for neoadjuvant plus adjuvant treatment in lung cancer; but it remains to be analyzed whether it is superior to nivolumab in neoadjuvant treatment alone, which involves less treatment and economic burden. As therapeutic positioning is always a necessary decision, whether made at a national, regional, local or individual level, it must be made in the most appropriate way. The absence of a multidisciplinary discussion and consensus, relying only on individual decisions to determine positioning from the outset, underestimates information gaps, inter-individual variability and the influence of drug promotion. It can be harmful and costly. To properly manage the introduction of new medicines, it is essential to establish their benefit scenario in a multidisciplinary way. This, together with consideration of the clinical benefit provided versus the appropriate alternatives and the uncertainties of the benefit, constitutes the objective of the clinical assessment and the basis for designing a well-focused economic analysis. This allows policy makers to make the most appropriate decisions on pricing and funding new treatments. In an ideal situation, the benefit scenario considered for the new medicine would coincide with the one established for funding, but costs that are difficult to bear may lead to restrictions and affect the final positioning after the economic and budgetary impact assessment.

Economic assessment of abemaciclib for the adjuvant treatment of luminal HER2- breast cancer from the perspective of the Spanish health system.

INTRODUCTION: Abemaciclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Data from the clinical trial monarchE (2023) showed improved survival from invasive disease. The aim of the present article was to conduct an economic assessment of adjuvant treatment with abemaciclib in women with luminal, HER2- and node-positive breast cancer. METHODS: A Markov model was constructed with four mutually exclusive health states (disease-free, local recurrence, distal recurrence and death). Analyses were based on the clinical trial monarchE which compared an intervention group (abemaciclib + hormone therapy [HT]) with HT alone. The effectiveness measure used was quality-adjusted life years (QALY), with unit costs and utilities being obtained from existing literature. The incremental cost-utility ratio (ICUR) was used to compare the two treatment strategies. RESULTS: Total costs were €98,765 and €17,935 for the abemaciclib plus HT group and the HT alone group, respectively. The health outcome was 10.076QALY for the intervention group and 9.495QALY for the control group, with the ICUR being€139,173/QALY. CONCLUSION: Despite the significant gains of abemaciclib as adjuvant treatment in terms of progression-free survival, this treatment is not cost-effective for the Spanish National Health System at published prices. It may be cost-effective with an appropriate discount on the official price.

Abemaciclib as adjuvant treatment for high-risk early breast cancer.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598-0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Abemaciclib as adjuvant treatment for high-risk early breast cancer. / [Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses.

INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19.

OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only  dexamethasone has clearly shown a reduction in mortality for COVID-19  hospitalized patients. For interleukin-6 inhibitors, results are variable and  nclear. The objective was to review and analyze the effect of tocilizumab and  sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A  systematic search in Medline, Embase and medRxiv was conducted to identify  randomized controlled trials with tocilizumab or sarilumab in hospitalized  patients with COVID-19. Mortality data from non-critical and critical patients  were extracted. A random-effects (DerSimonian-Laird) meta-analysis was  performed for both subgroups and the whole population using MAVIS software  v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase,  respectively, five were trials with tocilizumab and/or sarilumab; two more were  identified at medRxiv. Seven randomized clinical trials fulfilled the  inclusion criteria. Another trial was pre-published and included post-hoc. The  meta-analysis, with eight randomized clinical trials and 6,340 patients, showed  a benefit on mortality for interleukin-6  heterogeneity (I2 = 7%), but  a low similarity among studies. The results showed no differences among  critical and non-critical patients. A sensitivity analysis excluding non-similar or  heterogeneous studies showed different results, without benefit and with low  precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but  with important differences among the scenarios analyzed in the clinical  trials. Positive results are mainly caused by two randomized clinical trials which  are similar in concomitant use of steroids and veryhigh mortality in  critical patents. Sarilumab was poorly represented in the meta-analysis.  Nevertheless, an association between the benefit and the critical/non-critical  condition was not found. More randomized clinical trials, mainly focused in  atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis.

OBJETIVO: Un año después de la declaración de la pandemia por SARS­CoV-2,  solo dexametasona había mostrado claramente una reducción de la mortalidad  en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de  interleucina 6 son diversos y poco claros. El objetivo de este trabajo es  revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia  de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se  realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab  en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos  subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab;  se identificaron dos más en medRxiv. En total, siete ensayos clínicos  aleatorizados cumplieron los criterios de inclusión. Posteriormente, se  prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al  análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340  pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de  interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95% 0,74-0,99),  con baja heterogeneidad (I2 = 7%), pero reducida similitud entre los estudios.  Los resultados no mostraron diferencias entre pacientes críticos y no  críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no  similares mostró resultados diferentes, sin beneficio y con baja precisión del  resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de  la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se  eben principalmente a dos ensayos que son similares en el uso concomitante  de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre  el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en  pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los  inhibidores de interleucina-6 en COVID-19.

Factors associated with mortality in patients hospitalized for COVID-19 in Spain. Data from the RERFAR registry.

OBJECTIVE: To determine the baseline characteristics associated with higher  mortality at 42 days in patients hospitalized for COVID-19 in Spain. METHOD: The study analyzed a prospective cohort of hospitalized COVID-19  patients. The dependent variable was 42-day mortality. Data on the subjects'  demographic and clinical characteristics, comorbidities, usual therapy and  supportive interventions and treatments was collected within 48 hours from  admission. To determine the potential association of the data with mortality, a  multivariate analysis was performed using logistic regression. RESULTS: 15,628 patients were included, 18.2% of whom (n = 2,806) died  during the study period. According to the multivariate analysis, the variables  that were significantly associated (p < 0.05) with mortality upon admission  were: being referred from a nursing home (OR 1.9); having a high respiratory  rate (OR 1,5); having moderate (OR 1.7) or severe (OR 2.9) pneumonia  (CURB-65); aspartate aminotransferase transaminase ≥ 100 IU/l (OR 2.1);  lactate dehydrogenase ≥ 360 IU/L (OR 1.6); procalcitonin > 0.5 ng/mL (OR  1.8); creatine kinase ≥ 294 U/L (OR 1.5); D-dimer > 3,000 ng/mL (OR 1.5);  hemoglobin < 11.6 g/dL (OR 1.4) and C-reactive protein > 120 mg/L (OR 1.2;  requiring respiratory support within the first 48 hours (oxygen therapy [OR  2.0], non-invasive ventilation [OR 2.8], and mechanical ventilation [OR 3.5]);  and being treated with interferon-beta (OR 1.5). On the contrary, being under  80 years of age was associated with lower mortality. CONCLUSIONS: The analysis, based on the data in the RERFAR registry, showed that the factors associated with poorer prognosis were older age,  assessed using the CURB-65 scale, level of respiratory support required,  severe pneumonia (CURB-65), hypertransaminasemia, elevated creatine  kinase, lactate dehydrogenase, and D-dimer levels, anemia, and elevated  respiratory rate.

OBJETIVO: Determinar las características basales que se asocian a una mayor  mortalidad a los 42 días en aquellos pacientes hospitalizados por COVID-19 en  España.Método: Cohorte prospectiva de pacientes COVID-19 hospitalizados. La  variable dependiente fue la mortalidad a los 42 días. Además, se recogieron  características demográficas, clínicas, comorbilidades, tratamiento habitual,  intervenciones de soporte y tratamientos en las primeras 48 horas del ingreso.  Para determinar la asociación con la mortalidad, se realizó un análisis  multivariante mediante regresión logística. Resultados: Se incluyeron 15.628 pacientes, de ellos falleció el 18,2% (n =  2.806). El análisis multivariante mostró que las variables asociadas significativamente (p < 0,05) con la mortalidad al ingreso fueron:  proceder de un centro sociosanitario (odds ratio OR 1,9), frecuencia  respiratoria (odds ratio 1,5), gravedad de neumonía (CURB-65) moderada  (odds ratio 1,7) o alta (odds ratio 2,9), transaminasa aspartato  aminotransferasa ≥ 100 UI/l (odds ratio 2,1), lactato-deshidrogenasa ≥ 360  UI/l (odds ratio 1,6), procalcitonina > 0,5 ng/ml (odds ratio 1,8), creatina- quinasa ≥ 294 U/l (odds ratio 1,5), dímero D > 3.000 ng/ml (odds ratio 1,5),  hemoglobina < 11,6 g/dl (odds ratio 1,4) y proteína C reactiva > 120 mg/l  (odds ratio 1,2), necesidad de soporte respiratorio en las primeras 48 horas  (odds ratio 2,0 de oxigenoterapia; odds ratio 2,8 ventilación no invasiva y odds ratio 3,5 ventilación mecánica) y tratamiento con interferón-beta (odds ratio  1,5). Por el contrario, ser menor de 80 años se asoció a una menor mortalidad. Conclusiones: El análisis del Registro Español de Resultados de  farmacoterapia frente a COVID-19 muestra que los factores asociados a peor pronóstico son: mayor edad, valoración mediante la escala CURB­65, el nivel de requerimiento de soporte respiratorio, neumonía grave (CURB­65), hipertransaminasemia, elevación de creatina-quinasa, lactato- deshidrogenasa, y dímero-D, anemia y elevación de la frecuencia respiratoria.

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.

Cost-utility of talazoparib monotherapy treatment for locally advanced or metastatic breast cancer in Spain.

Breast cancer is one of the most frequent malignancies. The aim of the article is to analyse the cost-utility ratio and budgetary impact of talazoparib treatment for patients with locally advanced or metastatic gBRCA + breast cancer from the perspective of the Spanish National Health System. Analyses were based on the EMBRACA clinical trial and the model was constructed according to "partitioned survival analysis". Two scenarios were considered in order to compare talazoparib with the alternatives of capecitabine, vinorelbine and eribulin: 1. Chemotherapy in patients pre-treated with anthracyclines/taxanes and, 2. A second- and subsequent-line treatment option. Treatment types following relapse were recorded in the mentioned clinical trial. The effectiveness measure used was quality-adjusted life years (QALY). The average health cost of patients treated at 43 months with talazoparib was 84,360.86€, whilst current treatment costs were 26,683.90€. The effectiveness of talazoparib was 1.93 years of survival (1.09 QALY) relative to 1.58 years (0.83 QALY) in the treatment group. The incremental cost-utility ratio was 252,420.04€/QALY. This represents the additional cost required to earn an additional QALY when changing from regular treatment to talazoparib. Regarding budgetary impact, the number of patients susceptible to receiving treatment with between 94 and 202 talazoparib was estimated, according to scenario and likelihood. The 3-year cost difference was between 6.9 and 9 million euros. The economic evaluation conducted shows an elevated incremental cost-utility ratio and budgetary impact. Taking these results into account, the price of talazoparib would have to be lower than that taken as a reference to reach the cost-utility thresholds.

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.

Network meta-analysis of first-line treatments in transplant-ineligible multiple myeloma patients.

OBJECTIVES: Multiple myeloma (MM) is a complex disease. Lack of direct comparisons among treatments and incorporation of new alternatives make it necessary to perform studies that allow for clinical decision-making. A network meta-analysis (NMA) was developed to evaluate the comparative efficacy among different therapeutic alternatives in newly diagnosed transplant-ineligible MM patients. METHODS: MEDLINE® and EMBASE® were systematically searched up for these drugs: lenalidomide, thalidomide, bortezomib, and daratumumab. Comparative phase II-III randomized clinical trials (RCTs) were included. Progression-free survival (PFS) was selected as efficacy outcome. The NMA was developed using Bayesian methods. Fixed- and random-effects models were assessed using deviance information criteria. RESULTS: The systematic search yielded 593 results. Ten RCTs were included. No differences were observed between fixed- and random-effects models. The combination of daratumumab, bortezomib, melphalan, and prednisone showed the best HR in PFS (reference treatment). Along with this scheme, the best PFS results were obtained by combination of daratumumab, lenalidomide, and dexamethasone (HR 1.2, 95% CrI 0.64-2.4) and bortezomib with lenalidomide and dexamethasone (HR 1.6, 95% CrI 0.81-3.0). CONCLUSIONS: Schemes with the best PFS results were daratumumab treatments and combination of bortezomib, lenalidomide, and dexamethasone, although the latter scheme has been analyzed in heterogeneous populations.

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.

Drug evaluation is also a clinical activity.

The addition of a fourth year to the hospital pharmacy residency program has allowed trainees to rotate through various inpatient clinical  units where they can, under the supervision of a specialist pharmacist,  work shoulder to shoulder with other healthcare providers to ensure that  patients receive the care they need. In addition to sharing their  pharmacotherapeutic and pharmacokinetic knowledge (among others) with their colleagues, hospital pharmacists can and should contribute with their  expertise in the areas of drug evaluation, selection and positioning. As no  other healthcare professional masters like a pharmacist the intricacies of  treatment efficacy or effectiveness, or of therapeutic safety, conveying this knowledge is yet another of the many clinical activities a hospital  pharmacist must perform as a member of a multidisciplinary team, while  assisting fellow-team members in deciding what medications are best  suited to each patient. Both the public authorities and the pharmaceutical  profession as a whole should make sure the pharmacist's role is rightfully  valued and given the recognition it deserves.

La especialidad de Farmacia Hospitalaria incorporó con el cuarto año de su  programa formativo una parte importante de rotación por unidades clínicas de hospitalización en las que el farmacéutico en formación, acompañado  de farmacéuticos especialistas, tiene la oportunidad de trabajar  conjuntamente con otros profesionales en la atención directa al paciente.  Además de contribuir a esta atención con sus conocimientos de  farmacoterapia y farmacocinética, el farmacéutico de hospital puede y  debe aportar al equipo su liderazgo en evaluación, selección y posicionamiento de medicamentos. Ningún profesional conoce como él los aspectos relativos a la eficacia o efectividad, seguridad y eficiencia de los tratamientos, y estos conocimientos constituyen una actividad  clínica más de las que debe desempeñar en los equipos multidisciplinares,  ayudando a la toma de decisiones sobre medicamentos en cada paciente. Es necesario que tanto desde los organismos públicos como  desde nuestra propia profesión se ponga en valor este papel y que se  potencie de forma adecuada.

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.

Cost-effectiveness of lenalidomide maintenance in patients with multiple myeloma who have undergone autologous transplant of hematopoietic progenitor cells.

The objective of this article is to analyze the ratio of cost-effectiveness and budgetary impact of lenalidomide treatment in patients with multiple myeloma who have undergone autologous transplant in Spain. The analyses were based on clinical trials CALGB 100104 and IFM 2005-02, from the perspective of the National Health System. The alternatives compared were the treatment with lenalidomide against maintenance without treatment (MwT). Efficiency measures used were years of life gained (YGs) and quality-adjusted life years (QALYs). According to the CALGB 100104 trial data, the average health costs of patients who were treated with lenalidomide for 120 months was €836,534.31 and without treatment was €528,963.63. The effectiveness of the lenalidomide group was 7.59YGs (5.72 QALY) against 6.58 of MwT (4.61 QALY). The incremental cost-utility ratio (ICUR) was €277,456.72/QALY and the incremental cost-effectiveness ratio was €303,191.05/YGs. From the analysis, the IFM2005-02 trial obtained 5.13 QALY in the lenalidomide group against the 4.98 QALY in the MwT group, with an ICUR of €1,502,780.55/QALY. In terms of budgetary impact, a range between 799 and 1452 patients susceptible to receive treatment with lenalidomide was assumed in Spain. In conclusion, the results show a high ICUR and budgetary impact, which adds uncertainty about the maximum prudent duration of the treatment.

[Risk of medicines in pregnancy: a problem of knowledge transfer with ethical implications]. / Riesgo de medicamentos en el embarazo: un problema de transferencia del conocimiento con repercusiones éticas.

Drug use in pregnancy is essential and beneficial, but it is needed to check their safety. Available scientific evidence is poor and difficult to interpret. Risk classifications (FDA, ADEC) have shown to be too simple and categorical; they lead to inaccurate perceptions of risk and unfortunate decisions, such as interrumption of medication, or abortion. This has become clear with antidepressants or the antiretroviral efavirenz. Although abortion is not justified, misinformation contributes even more to the problem. Information tends to obviate that not every risk in pregnancy is teratogenic, that the existence of risk does not imply high probability, and that the nature and probability of the risk vary according to the stage.

Cost-effectiveness and Budget Impact of Treatment with Evolocumab Versus Statins and Ezetimibe for Hypercholesterolemia in Spain.

INTRODUCTION AND OBJECTIVES: To analyze the cost-effectiveness ratio and budget impact of treatment with evolocumab (PCSK9 inhibitor) for patients in secondary prevention in the Spanish National Health System. METHODS: A budget impact analysis, decision tree and Markov models were designed under the public health system perspective, based on the only study with morbidity and mortality data (FOURIER). The alternatives compared were evolocumab vs statins, and dual therapy with ezetimibe in 5% of the population. The measure of effectiveness used was the number of cardiovascular events avoided. Univariate and probabilistic sensitivity analyses were performed. RESULTS: The average annual cost of patients receiving evolocumab was 11 134.78€ and 393.83€ for standard treatment (statins plus ezetimibe). The incremental cost-effectiveness ratio was > 600 000 € per avoided cardiovascular event for both assessed outcomes (first: cardiovascular death, myocardial infarction, stroke, and hospitalization due to unstable angina or coronary revascularization; second: includes the first 3 events). To perform the 10-year Markov model, the average cost of standard treatment was 13 948.45€ vs 471 417.37€ with evolocumab. Treatment with evolocumab for patients with familial hypercholesterolemia would cost between 3 and 6.1 million euros, assuming a difference of 2.5 and 5.1 million euros with the standard treatment (2017). This difference would be between 204.3 and 1364.7 million euros (2021) for those with nonfamiliar hypercholesterolemia (secondary prevention). CONCLUSIONS: Treatment with evolocumab is associated with a lower frequency of cardiovascular events, but is inefficient for patients suitable to receive this drug in the Spanish National Health System.