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.

Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission. / Evolución tras el intercambio a infliximab biosimilar en pacientes con enfermedad inflamatoria intestinal en remisión clínica.

BACKGROUND AND AIM: The biosimilar of infliximab (CT-P13) has been approved for the same indications held by the infliximab reference product (Remicade®); however, there are few clinical data on switching in inflammatory bowel disease (IBD). The aim of this study was to assess the efficacy, safety, bioavailability profile and factors associated with relapse after switching to biosimilar infliximab in IBD patients in clinical remission. MATERIAL AND METHOD: Observational study with IBD patients treated with Remicade® for at least 6 months and in clinical remission for at least 3 months who switched to infliximab biosimilar. The incidence of relapse, adverse effects and possible changes in drug bioavailability (trough level and antidrug antibodies) were evaluated. RESULTS: Thirty six patients were included (63.9% CD) with a mean follow-up of 8.4 months (SD±3.5). The 13.9% had clinical relapse. The longer clinical remission time before switching (HR=0.54, 95% CI=0.29-0.98, P=.04) and detectable infliximab levels at the time of switching (HR=0.03, 95% CI=0.001-0.89, P=.04) were associated with a lower risk of relapse. No differences were found between infliximab levels at the time of switching and at weeks 8 and 16 (P=.94); 8.3% of the patients had some adverse event, requiring the suspension of biosimilar in one patient for severe pneumonia. CONCLUSION: Switching to biosimilar infliximab in a real-life cohort of IBD patients in clinical remission did not have a significant impact on short-term clinical outcomes. The factors associated with relapse were similar to those expected in patients continuing with Remicade®.

Assessment of off-label prescribing: profile, evidence and evolution.

OBJECTIVES: The objectives of the study were to describe the extent and profile of off-label prescriptions, to evaluate the level of evidence supporting these indications, to assess the research activity in these conditions, and to determine to what extent these were authorized as new indications five years after the application. METHODS: A cross-sectional study including all applications conducted in the Hospital Universitario Reina Sofía in Córdoba during 2010. ANALYSIS:  level of evidence according to the criteria by SIGN-NICE (Scottish Intercollegiate Guidelines Network, National Institute for Health and Care Excellence) and CEBM (Centre for Evidence-based Medicine), registered clinical trials (source: ClinicalTrials.gov), and review of product specifications and monthly newsletters from the Spanish Agency of Medicines and Medical Devices. RESULTS: There were 190 applications for off-label prescription for 82 different indications. The most requested medications were: tacrolimus, mycophenolate, colistimethate and everolimus; the immunosuppressant group had the highest number of uses for non-approved indications. Out of the applications, 52.4% were based on some clinical trial, while the rest had a low level of evidence (observational studies and case reports). We have found on-going clinical trials for 67% of the indications, but new indications in their product specifications have only been authorized for nine drugs (bevacizumab, deferasirox, everolimus, lenalidomide, methotreate, sildenafil, sorafenib, raltegravir and tenofovir). CONCLUSIONS: We have detected a major volume of off-label prescription without good supporting evidence, which identifies these indications and medications as interesting research lines, but that require follow-up in terms of effectiveness and costs.

Objetivo: Los objetivos del estudio fueron describir la magnitud y el perfil de las prescripciones fuera de ficha técnica (off-label), evaluar el nivel de evidencia en el que se sustentan estas indicaciones, valorar la actividad investigadora en estas enfermedades y determinar en qué grado se autorizan como nuevas indicaciones transcurridos cinco años desde la solicitud.Métodos: Estudio transversal que incluyó todas las solicitudes realizadas en el Hospital Universitario Reina Sofía de Córdoba durante 2010. Análisis: nivel de evidencia según criterios de SIGN-NICE (Scottish Intercollegiate Guidelines Network, National Institute for Health and Care Excellence) y del CEBM (Centre for Evidence-based Medicine), ensayos clínicos registrados (fuente: ClinicalTrials.gov) y la revisión de fichas técnicas e informes mensuales de la Agencia Española del Medicamento.Resultados: Hubo 190 solicitudes off-label para 82 indicaciones distintas. Los medicamentos más solicitados fueron tacrolimus, micofenolato, colistimetato y everolimus, constituyéndose el grupo de inmunosupresores como el de mayor número de usos en indicaciones no aprobadas. El 52,4% de las solicitudes estaban basadas en algún ensayo clínico, mientras que el resto tuvo un bajo nivel de evidencia (estudios observacionales y casos). Hemos encontrado ensayos clínicos en activo para el 67% de las indicaciones, pero solo nueve fármacos han visto autorizadas nuevas indicaciones en su ficha técnica (bevacizumab, deferasirox, everolimus, lenalidomida, metotrexato, sildenafilo, sorafenib, raltegravir y tenofovir).Conclusiones: Se ha detectado un importante volumen de usos offlabel en ausencia de buena evidencia, lo que identifica a estas indicaciones y medicamentos como líneas de investigación interesantes pero con necesidad de seguimiento de efectividad y costes.