Protocolo de optimización de uso de medicamentos biológicos en enfermedades inflamatorias inmunomediadas / Protocol for optimization of the use of biological drugs in immune-mediated inflammatory diseases

Objetivo: La artritis reumatoide (AR), espondilitis anquilosante, psoriasis (Ps), artritis psoriásica (APs) están mediadas por factor de necrosis tumoral (TNF). El objetivo es el diseño multidisciplinar de un protocolo personalizado de agentes biológicos en enfermedades reumáticas y dermatológicas. Métodos: Se seleccionaron pacientes con AR, APs, espondiloartritis y Ps que recibían etanercept o adalimumab durante al menos 6 meses ininterrumpidamente. La monitorización terapéutica consideró criterios bioquímicos y criterios clínicos. Rangos terapéuticos óptimos de adalimumab: 5-8 μg/mL para AR y APs, 3.2-7 μg/mL para Ps y 4.6-12 μg/mL para espondiloartritis. Rangos óptimos de etanercept fueron: 2-3 μg/mL para AR y espondiloartritis, y 2-7 μg/mL para Ps y APs. Resultados: Se realizaron propuestas de optimización del tratamiento en pacientes con adecuada respuesta clínica y niveles de fármaco biológico superiores al rango terapéutico óptimo. Si la propuesta de optimización fue aceptada por facultativo, se valoró percepción de la enfermedad del paciente al primer y tercer mes. Los pacientes con niveles plasmáticos de fármaco inferiores al rango terapéutico óptimo, ausencia de anticuerpos anti-fármaco y adecuada respuesta clínica fueron propuestos a optimización de tratamiento mediante discontinuación o espaciamiento de administración. Los pacientes con niveles plasmáticos de fármaco inferiores al rango óptimo y anticuerpos anti-fármaco fueron propuestos a cambio de tratamiento o discontinuación, si se pudiera alcanzar control de enfermedad. Conclusiones: Este protocolo permite la personalización terapéutica de etanercept y adalimumab para enfermedades inflamatorias inmunomediadas en áreas de dermatología y reumatología. La implantación del protocolo podría mejorar la eficacia, seguridad, conveniencia y eficiencia de etanercept y adalimumab. (AU)

Objective: Rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis (Ps), psoriatic arthritis (PAs) are mediated by tumor necrosis factor (TNF). The objective is the multidisciplinary design of a personalized protocol of biological agents in rheumatic and dermatological diseases. Methods: Patients with RA, PAs, spondyloarthritis and Ps receiving etanercept or adalimumab for at least 6 months uninterruptedly were selected. Therapeutic monitoring considered biochemical criteria and clinical criteria. Optimal therapeutic ranges of adalimumab were: 5-8 μg/mL for RA and APs, 3.2-7 μg/mL for Ps and 4.6-12 μg/mL for spondyloarthritis. Optimal ranges of etanercept were: 2-3 μg/mL for RA and spondyloarthritis, and 2-7 μg/mL for Ps and APs. Results: Proposals were elaborated to optimize treatment in patients with adequate clinical response and levels of biological drug higher than the optimal therapeutic range. If the optimization proposal was accepted by the physician, the patient’s perception of disease was evaluated at the first and third months. Patients with plasma drug levels below the optimal therapeutic range, absence of anti-drug antibodies and adequate clinical response were proposed for treatment optimization by discontinuation or spacing of administration. Patients with plasma drug levels below the optimal range and anti-drug antibodies were proposed in exchange for treatment or discontinuation -if disease control could be achieved-. Conclusions: This protocol allows the therapeutic personalization of etanercept and adalimumab for immune-mediated inflammatory diseases in areas of dermatology and rheumatology. Implementation of the protocol could improve the efficacy, safety, convenience and efficiency of etanercept and adalimumab. (AU)

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)

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.

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.

[Erythropoietin: a study of its use in oncohematology]. / Eritropoyetina: estudio de utilización en oncohematología.

OBJECTIVE: To assess the effectiveness of erythropoietin (EPO) in a Clinical Oncohematology Unit within a general hospital, and to propose a therapeutic algorithm with EPO based on recommendations by ASCO. MATERIAL AND METHODS: A descriptive, retrospective study was carried out on patients who required support treatment with EPO while in the Oncohematology Unit during the year 2001. Data were collected by reviewing patient medical records. An effective treatment was defined as an increase in baseline hemoglobin (Hb) equal to or higher than 2 g/dL over 4-8 weeks, with no transfusion requirements or decreased transfusion needs. Baseline Hb values, their distribution per diagnosis, and the involvement of platinum-containing chemotherapy regimens were analyzed. RESULTS: Of the 353 patients in chemotherapy, 87% corresponded to oncologic diagnoses while the rest had hematological neoplasms. A total of 54 patients were assessed, with 83% of these corresponding to the oncologic area. Oncologic diagnoses that most required the use of EPO included: head-neck 53%, genitourinary 39%, and lung 39%. Overall effectiveness was 57% (60% in oncology and 44% in hematology). The Hb value leading to initial prescription (baseline Hb) was always below 10 g/dL for the hematology area, whereas most oncology patients exhibited higher levels at therapy onset. CONCLUSIONS: 1. Its percentage of failure: 40% for oncology and 56% for hematology patients, together with its high cost, shows that a further search for predictive factors is warranted in order to more precisely select individuals who may benefit from this therapy. 2. The percentage of oncology patients with baseline Hb <10 is only 29%. Baseline Hb values for treatment onset and peak Hb values for therapy discontinuation should be agreed upon. Treatment initiation when Hb values fall below 10 g/dL would be a reasonable option, and a decision to use EPO above 10 g/dL should be made in patients with less severe anemia (10-12 g/dL) only if clinical circumstances render it advisable. 3. Use protocols must include clear concept definitions for treatment, and for primary and secondary prophylaxis, which will help in the establishment of therapeutic algorithms.

[Pharmaceutical intervention for the optimisation of outpatient drug prescription in a hospital Emergency Department]. / Intervención farmaceútica para optimizar la prescripción externa de medicamentos en un Servicio de Urgencias hospitalario.

OBJECTIVE: To discuss various aspects of drug prescription for first-year resident physicians (MIR-1) working in Emergency Departments in order to promote a rational use of drugs, and to assess the impact of such pharmaceutical intervention. METHOD: During personal interviews MIR-1s were briefed (both orally and in written form) on prescription characteristics of their department. Both qualitative (compliance with the Pharmaco-therapeutic Guide, prescription of drugs with low intrinsic value) and quantitative (prescription profile for medicines with the same active principle but different price) parameters were discussed. Then the impact of these interviews was analysed by comparing outpatient prescriptions by MIR-1s during August-November 2000 versus those filled by their colleagues during this same period in 1998 and 1999. RESULTS: Outpatient prescriptions by the MIR-1 group conformed better to the qualitative and quantitative parameters studied. Despite such better results, greater savings may still be obtained by improving quinolone/macrolide, anti-ulcer drug, ACE inhibitor and NSAID prescriptions, since these amount to 93% of total potential savings. DISCUSSION: By conducting personal interviews with a pharmacist new MIR-1s encounter an additional information source contributing to more sensible drug prescriptions.