Evaluación de los comparadores empleados en los estudios pivotales de nuevos medicamentos e indicaciones / Assessment of comparators used in pivotal studies of new medicines and indications

Objetivo: En algunos casos, los estudios pivotales para aprobar nuevos medicamentos no emplean el comparador más adecuado. El objetivo es cuantificar este problema analizando los Informes de Posicionamiento Terapéutico (IPT) publicados por el Ministerio de Sanidad español.Métodos: El comparador se clasificó en seis categorías según la adecuación del tratamiento, es decir, si coincidía con el estándar de tratamiento al ser autorizado: A-“inicialmente adecuado”, B-“sin comparador por causa ética”, C-“sin comparador excluyendo los clasificados en B”, D-“inadecuado” y E-“parcialmente subóptimo” (cuando era estándar solo para parte de los pacientes).La variable principal fue la proporción de nuevos fármacos/indicaciones con comparación suficiente (categorías A, B y C) o deficiente (el resto). La información sobre comparadores y tratamiento estándar se extrajo del IPT. Resultados: Se analizaron aleatoriamente 186 IPT con nuevos medicamentos/indicaciones, publicados entre 2013 y 2022. La comparación se consideró suficiente en un 73,7% (IC95 66,9-79,5) de los casos. El 26,3% restante (IC95 20,5-33,1) presentaba comparaciones deficientes en el ensayo pivotal, ya fuera por comparador inadecuado (11,3%), parcialmente subóptimo (5,4%) o ausencia de un estudio comparativo (9,7%). No hubo diferencias en relación con el año de aprobación.Conclusiones: Aproximadamente uno de cada cuatro nuevos medicamentos o indicaciones carece de una comparación suficiente en el momento de empezar a ser utilizado en la práctica clínica. La proporción no mejora a lo largo de los últimos 10 años. Las agencias reguladoras deben ser más exigentes en la selección del comparador para los ensayos clínicos pivotales, por cuestiones éticas y sanitarias. (AU)

Objective: Pivotal studies to approve new medicines often do not use the most appropriate comparator. The objective is to quantify this problem by analysing the Therapeutic Positioning Reports (IPT for its acronym in Spanish) published by the Spanish Health Ministry.Methods: The comparator was classified into six categories, based on the appropriateness of the treatment, i.e. whether it matched the standard of treatment when authorised: A-«initially adequate» (at the start of the study), B-«no comparator for ethical reasons», C-«no comparator -excluding B-«, D-«inadequate» and E-«partially suboptimal» (when it was standard for part of the included patients but not for all of them).The primary endpoint was the proportion of new drugs/indications with sufficient (categories A, B and C) or poor comparator (the rest). Information on comparators and standard treatment was extracted from the IPT. Results: We randomly analysed 186 IPTs with new drugs or indications, published between 2013 and March 2022. Comparability was assessed as sufficient in 73.7% (95%CI 66.9-79.5) of cases. The remaining 26.3% (95%CI 20.5-33.1) had poor comparisons in the pivotal trial, either due to inadequate comparator (11.3%), partially suboptimal (5.4%) or absence of a comparative study excluding ethical justification (9.7%). Conclusions: Approximately one in four new medicines or indications lacks sufficient comparability at the time of entry into clinical practice. The proportion has not improved over the last 10 years. Regulatory agencies need to be more stringent in comparator selection for pivotal clinical trials, for ethical and health reasons. (AU)

Efficacy of early use of remdesivir: a systematic review of subgroup analysis.

OBJECTIVE: A possible benefit has been suggested for early treatment of severe coronavirus disease 2019 (COVID-19) with remdesivir. The efficacy of this drug is controversial and could significantly influence the efficiency in healthcare systems. The objective is the methodological interpretation of subgroup analyzes according to starting of remdesivir treatment with respect to symptom onset of COVID-19. METHODS: A search in Pubmed® database was performed. Randomized clinical trials (RCTs) with subgroup analysis regarding early and late use of remdesivir were selected. All endpoints were assessed using two methodologies. First methodology considered statistical interaction, pre-specification, biological plausibility, and consistency of results. Second methodology was a validated tool with preliminary questions to discard subset analysis without relevant minimum conditions, and a checklist with recommendations for applicability. RESULTS: A total of 54 results were found and five RCTs were selected. According first methodology, consistent heterogeneity was only found in time to clinical improvement and better clinical status score at day 15 for patients with severe COVID-19 and <7 days of symptoms. About second methodology, these results about early use of remdesivir may be applied to clinical practice with caution. CONCLUSIONS: We developed a systematic search and application of an established methodology for interpretation of subgroup analysis about early use of remdesivir. Results in severe COVID-19 suggested that early use of remdesivir provides a greater benefit in <7 days of symptoms for time to clinical improvement and better clinical status score at day 15. Future studies could use 7-day cut-off of symptoms to evaluate remdesivir.

Safety considerations during prescription of non-steroidal anti-inflammatory drugs (NSAIDs), through a review of systematic reviews.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide. This makes it necessary to carry out a comprehensive synthesis of the available evidence on the safe and adequate prescription of NSAIDs in patients with cardiovascular disease, chronic kidney disease, hypertension, heart failure or liver cirrhosis and in general population. For this, a review of systematic reviews was carried out. Data extraction and analysis were performed independently by two reviewers and a narrative synthesis of the results was carried out. The use of NSAIDs is associated with a significantly higher probability of hepatotoxicity and kidney damage, as well as increased risk of exacerbation of heart failure. Taking into account the increased cardiovascular, liver and kidney risk, the prescription of NSAIDs should be carried out with caution, considering the treatment duration and the patient's situation. For this reason, patients should be informed about their possible health consequences as well as ensuring adequate monitoring of them.

Expresiones y criterios mejorables en la redacción de informes de evaluación y posicionamiento terapéutico / Expressions and criteria that could be improved in the writing of reports for drug evaluation and therapeutic positioning

En la revisión de borradores de informes para evaluación y posicionamiento de nuevos fármacos en un entorno multidisciplinar, se observan determinados errores de expresión o criterio que se repiten con frecuencia. Principalmente, están relacionados con la consideración de “diferencias” o tendencias no significativas, abuso de la reducción relativa del riesgo, errores en la valoración de resultados por subgrupos sin calcular la interacción estadística, confusiones en la interpretación de las comparaciones indirectas, sobrevaloración de la relevancia clínica con variables subclínicas y afirmaciones sesgadas en el apartado de seguridad, entre otros. También se observa a menudo ambigüedad o inhibición en el posicionamiento, especialmente en situaciones de precariedad en la evidencia disponible. El presente trabajo expone de forma sintética tales errores, aclara algunos términos comunes y propone expresiones o criterios alternativos que se consideran preferibles, con el fin de ofrecer una evaluación para la toma de decisiones en beneficio de los pacientes. (AU)

In the review of reports for evaluation and positioning of new drugs in a multidisciplinary setting, some usual errors of expression or criteria are observed. Most of them are related to the consideration of «differences» or non-significant trends, abuse of the relative risk reduction, errors in the assessment of results by subgroups without calculating the statistical interaction, misinterpretation of indirect comparisons, excess in the assessment of clinical relevance with subclinical variables and biased statements in the safety section, among others. Ambiguity or inhibition in positioning is also often observed, especially in situations of precariousness in the available evidence. This work summarizes such errors, clarifies some common terms and proposes alternative expressions or criteria that are considered preferable, in order to offer evaluations for decision-making focused on the benefit of patients. (AU)

New graphic AUC-based method to estimate overall survival benefit: pomalidomide reanalysis.

WHAT IS KNOWN AND OBJECTIVE: Difference in median survival is an erratic measure and sometimes does not provide a good assessment of survival benefit. The aim of this study was to reanalyse the overall survival benefit of pomalidomide from pivotal clinical trial using a new area under curve (AUC)-based method. COMMENT: In the pivotal trial, pomalidomide plus low-dose dexamethasone showed a significant survival benefit over high-dose dexamethasone, with a difference between medians of 4.6 months. The new AUC method applied to the survival curves, obtained an overall survival benefit of 2.6 months for the pomalidomide treatment. This average difference in OS was calculated for the 61.5% of patients for whom the time to event is reliable enough. WHAT IS NEW AND CONCLUSION: This 2-month differential would have major clinical and pharmacoeconomic implications, on both cost-effectiveness studies and on the willingness of the healthcare systems to pay for this treatment.

A checklist for critical appraisal of indirect comparisons.

The aim of this study was to develop a user-friendly checklist for critical appraisal of indirect comparisons of drugs, considering clinical, methodological/statistical and quality aspects, mainly to be applied in drug evaluation in the decision-making context. After conducting a review of the literature, we used group consensus to establish the key points of the checklist, focusing mainly on indirect comparisons, but including topics related to network meta-analysis or multiple treatment comparisons. The coordinating group elaborated the first draft, which was reviewed by external experts, re-evaluated by the coordinating group and finally assessed by 23 drug evaluation experts trained in indirect comparisons, who applied the checklist to one study. The Kappa index of agreement was calculated and the final checklist was developed by group consensus including the external experts. The checklist has two parts. The first consists of three eliminatory key questions while the second includes 17 items: 5 regarding quality, 5 regarding clinical issues and 7 dealing with methodology/statistics. The median kappa values of the 23 evaluations were 0.83 (range 0.67-0.93), 0.61 (0.54-0.91) and 0.36 (0.22-1) with regard to quality, clinical aspects and methodology/statistics, respectively. A structured checklist was developed to facilitate critical appraisal of key issues in indirect comparisons, including comments for assessing the consequences of its application to drug evaluation in the decision-making context. Agreement between reviewers in clinical and quality items was good, but weaker in methodology/statistics ones.

Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis.

WHAT IS KNOWN AND OBJECTIVE: Psoriatic arthritis is an autoimmune disease characterized by chronic inflammation of the skin and joints. Anti-TNF drugs reduce the severity of the disease in the long term. This study compares the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in patients with psoriatic arthritis. METHODS: Direct comparison was based on a literature search of drug comparison studies, whereas indirect treatment comparison was based on phase III clinical trials with biological agents, involving similar populations and durations, and with the same outcome. ACR50 was taken as primary outcome for comparison, whereas ACR20 and ACR70 were used as secondary outcomes. Indirect comparisons were made using infliximab as the reference drug and the Bucher method. In calculating δ (the maximum acceptable difference as a clinical criterion of equivalence), use was made of half of the absolute risk reduction obtained in the meta-analysis of the clinical trials included in the indirect comparison (ARR 32%; δ: 16%). The four anti-TNF drugs were also compared in relation to the secondary outcomes and adverse effects. RESULTS AND DISCUSSION: Reported direct and indirect comparisons of the four drugs did not include golimumab, and did not yield conclusive results. Four clinical trials - one for each drug studied - were identified. The estimated differences for the primary outcome, ACR50, between infliximab and the other drugs were adalimumab (ARR 4%, 95% CI -9·5 to 17·5), etanercept (ARR 4%, 95% CI -10·5 to 18·5) and golimumab (ARR 9%, 95% CI -5·4 to 23·4). Likewise, there were no relevant differences between the drugs in relation to the secondary efficacy outcomes, except for etanercept, which was less effective in ACR70 response. For adverse reactions, there were also no significant differences except for injection site, reactions which were more frequent with etanercept, with a mean difference of 26% relative to infliximab. WHAT IS NEW AND CONCLUSION: No significant differences were found in ACR50 responses to the four drugs after 24 weeks. Injection-site reactions were more common with etanercept, but this was insufficient to invalidate the inference that clinically the four drugs can be regarded as clinically equivalent for the treatment of psoriatic arthritis.

Antagonistas de los receptores de la angiotensina II en el manejo de la enfermedad cardiovascular: ¿cuál es su lugar en la terapéutica? Resumen de los ensayos clínicos más relevantes / Angiotensin II receptor antagonists in the management of cardiovascular disease: a summary of the most relevant clinical trials and the place of these drugs in therapeutics

Los antagonistas de los receptores de la angiontensina II (ARA II) son un subgrupo de antihipertensivos muy polémicos desde su comercialización, tanto por su elevado precio como por la gran presión promocional dela industria farmacéutica a todos los niveles, pero también por su lugar en la terapéutica de las indicacionesautorizadas. En la actualidad su uso se ha extendido, y han logrado desplazar a otros subgrupos terapéuticos,en particular a los inhibidores de la enzima conversora de la angiotensina (IECA), sin que este hechoesté basado en evidencias sólidas. El objetivo de esta revisión es analizar los ensayos clínicos más importantesrealizados con los ARA II, resumir su contenido en forma de tablas para facilitar su consulta por partede los farmacéuticos de atención primaria en su quehacer diario, y determinar el lugar que ocupan en laterapéutica estos fármacos en sus distintas indicaciones a partir de dichos estudios

Drugs containing angiotensin II (AII) receptor antagonists are a subgroup of antihypertensive agents thathave been highly controversial ever since they became commercially available because of their high cost, themarked promotional pressure exerted at every level by the pharmaceutical industry and their place in therapeuticswith respect to the approved indications. At the present time, their use has become increasinglywidespread, displacing other therapeutic subgroups, especially angiotensin converting enzyme (ACE) inhibitors,despite the absence of solid evidence-based reasons. The objective of the present review is to analyzethe most important clinical trials carried out with AII receptor agonists, summarize their content in tableform for use by primary care pharmacists in their routine practice and determine the place of these drugsin the treatment of the conditions for which they are indicated, according to said studies

Asistencia farmacéutica a la prescripción para aproximar la práctica clínica a la evidencia científica / Attention to pharmaceutical prescriptions to bring clinical practice into line with scientific evidence

Objetivo. El objetivo del presente estudio es valorar la utilidad de un programa de asistencia farmacéutica a la prescripción (AFP) en cuanto a la detección de problemas relacionados con los medicamentos. Diseño. Realizamos un estudio descriptivo de los hallazgos de este programa al cabo de 6 meses de rodaje. Emplazamiento. El trabajo fue realizado en 5 centros del Distrito Bahía-Cádiz de Atención Primaria. Pacientes. Se estudian todos los pacientes (499) incluidos a petición y criterio de su médico, que solicita asesoramiento sobre su farmacoterapia. Intervención. Implantamos el programa de AFP en pacientes crónicos con dos finalidades básicas: 1. Asistencial: detectar problemas relacionados con medicamentos y proponer soluciones individualizadas. 2. Docente: aproximar los conocimientos en farmacoterapia aplicados en la práctica clínica a la evidencia científica disponible. Mediciones y resultados. Nos centramos en la detección de aquellos problemas relacionados con medicamentos más frecuentes, con incidencia directa y relevante sobre la morbimortalidad. Detectamos 236 casos (47 por ciento) de posible mejora terapéutica con implicaciones importantes sobre morbilidad asociada, de los cuales 114 (23 por ciento) tenían también implicaciones sobre mortalidad. Un 56 por ciento de los pacientes recibía más de 4 medicamentos, polimedicación que podía reducirse fácilmente en un 43,5 por ciento de ellos, evitando la utilización de medicamentos de valor intrínseco no elevado. Conclusiones. La utilidad del programa resulta muy elevada al detectar numerosos problemas de gran relevancia clínica y aportar información que puede ser útil al médico para aproximar la farmacoterapia a la evidencia científica disponible (AU)