Consensus statement on the use of biosimilar drugs in immune-mediated diseases in Spain.

OBJECTIVE: To improve knowledge about biosimilar medicines and to generate a consensus framework on their use. METHODS: Qualitative study. A multidisciplinary group of experts in biosimilar medicines was established (1dermatologist, 1hospital pharmacist, 1rheumatologist, and 1gastroenterologist) who defined the sections and topics of the document. A narrative literature review was performed in Medline to identify articles on biosimilar medicines. Systematic reviews, controlled, pre-clinical, clinical, and real-life studies were selected. Based on the results of the review, several general principles and recommendations were generated. The level of agreement was tested in a Delphi that was extended to 66 health professionals who voted from 1 (totally disagree) to 10 (totally agree). Agreement was defined if at least 70% of the participants voted ≥7. RESULTS: The literature review included 555 articles. A total of 10 general principles and recommendations were voted upon. All reached the level of agreement established. The document includes data on the main characteristics of biosimilar medicines (definition, development, approval, indication extrapolation, interchangeability, financing, and traceability); published evidence (biosimilarity, efficacy, effectiveness, safety, immunogenicity, efficiency, switch); barriers and facilitators to its use; and data on information for patients. CONCLUSIONS: Authorized biosimilar medicines meet all the characteristics of quality, efficacy, and safety. They also significantly help improve patient access to biological therapies and contribute to health system sustainability.

Documento de consenso sobre los medicamentos biosimilares en enfermedades inmunomediadas en España / Consensus statement on the use of biosimilar drugs in immune-mediated diseases in Spain

Objetivo: Mejorar el nivel de conocimiento sobre los medicamentos biosimilares y generar un marco consensuado sobre su uso. Métodos: Estudio cualitativo. Se seleccionó un grupo multidisciplinar de expertos en medicamentos biosimilares (una dermatóloga, un farmacéutico de hospital, un reumatólogo y un gastroenterólogo) que definieron los apartados y los temas del documento. Se realizó una revisión narrativa de la literatura en Medline para identificar artículos sobre los medicamentos biosimilares. Se seleccionaron revisiones sistemáticas de la literatura, estudios controlados pre-clínicos, clínicos y en vida real. Con esta información se generaron varios principios generales y recomendaciones. El grado de acuerdo con los mismos se estableció mediante un Delphi que se extendió a 66 profesionales de la salud que votaron de 1 (totalmente en desacuerdo) a 10 (totalmente de acuerdo). Se definió acuerdo si al menos el 70% de los participantes votaron ≥7. Resultados: La revisión de la literatura incluyó 555 artículos. Se votaron un total de 10 principios generales y recomendaciones. Todos alcanzaron el nivel de acuerdo establecido en el Delphi. El documento incluye datos sobre las características principales de los medicamentos biosimilares (definición, desarrollo, aprobación, extrapolación de indicaciones, intercambiabilidad, financiación y trazabilidad); sobre la evidencia publicada (biosimilitud, eficacia, efectividad, seguridad, inmunogenicidad, eficiencia, switch); sobre barreras y facilitadores a su uso, y datos sobre la información para pacientes. Conclusiones: Los medicamentos biosimilares autorizados reúnen todas las características de calidad, eficacia y seguridad. Además, ayudan significativamente a mejorar el acceso de los pacientes a las terapias biológicas y contribuyen a la sostenibilidad de los sistemas sanitarios. (AU)

Objective: To improve knowledge about biosimilar medicines and to generate a consensus framework on their use. Methods: Qualitative study. A multidisciplinary group of experts in biosimilar medicines was established (1dermatologist, 1hospital pharmacist, 1rheumatologist, and 1gastroenterologist) who defined the sections and topics of the document. A narrative literature review was performed in Medline to identify articles on biosimilar medicines. Systematic reviews, controlled, pre-clinical, clinical, and real-life studies were selected. Based on the results of the review, several general principles and recommendations were generated. The level of agreement was tested in a Delphi that was extended to 66 health professionals who voted from 1 (totally disagree) to 10 (totally agree). Agreement was defined if at least 70% of the participants voted ≥7. Results: The literature review included 555 articles. A total of 10 general principles and recommendations were voted upon. All reached the level of agreement established. The document includes data on the main characteristics of biosimilar medicines (definition, development, approval, indication extrapolation, interchangeability, financing, and traceability); published evidence (biosimilarity, efficacy, effectiveness, safety, immunogenicity, efficiency, switch); barriers and facilitators to its use; and data on information for patients. Conclusions: Authorized biosimilar medicines meet all the characteristics of quality, efficacy, and safety. They also significantly help improve patient access to biological therapies and contribute to health system sustainability. (AU)

Medicamentos bioterapéuticos: uso de toxinas botulínicas en la era de biosimilares / Biotherapeutic medicines: use of botulinum toxins in the era of biosimilars

Introducción: Las toxinas botulínicas son medicamentos bioterapéuticos con grandes aplicaciones en el campo de la neurología, como la cefalea y los movimientos anormales. Debido a la importancia médica y al incremento de las indicaciones terapéuticas de la toxina botulínica, este artículo pretende hacer claridad acerca de la terminología básica con respecto a la naturaleza de este medicamento, a las diferencias estructurales con medicamentos convencionales y aspectos importantes en relación con su potencia biológica e inmunogenicidad, para así comprender las potenciales diferencias entre las toxinas disponibles y conceptuar en torno a la no intercambiabilidad o sustitución de una toxina por otra. Materiales y métodos: Revisión no sistemática, según lo recomendado en la Escala para la Verificación de los Artículos Revisiones Narrativas (Sanra). Conclusiones: Los medicamentos biológicos no son intercambiables entre sí, aunque demuestren bioequivalencia. No se pueden evaluar como medicamentos genéricos intercambiables porque son biológicos; no existen estudios comparativos cabeza a cabeza; son diferentes, debido al proceso individual de manufactura.

Introduction: Botulinum toxins are biotherapeutic drugs with great applications in the field of neurology such as headache and abnormal movements. Due to the medical importance and the increase in therapeutic indications of botulinum toxin, this article aims to clarify the basic terminology regarding the nature of this drug, the structural differences with conventional drugs and important aspects in relation to its biological potency and immunogenicity in order to understand the potential differences between the available toxins and conceptualize regarding the non-interchangeability or substitution of one toxin for another. Materials and methods: Non-systematic review as recommended in the Scale for the Verification of Narrative Review Articles (SANRA). Conclusions: Biological drugs are not interchangeable with each other, even if they demonstrate bioequi-valence. They cannot be evaluated as interchangeable generic drugs because they are biologics. There are no head-to-head comparative studies. They are different due to the individual manufacturing process.

Estudio comparativo de la calidad biofarmacéutica de Diazepam 10 mg comercializados en el mercado peruano / Comparative study of the biopharmaceutical quality of Diazepam 10 mg commercialized in the Peruvian market

Introducción: el Diazepam pertenece a un grupo de medicamentos llamados benzodiazepinas. Se sabe que estos medicamentos actúan en el cerebro a través del GABA. Se utiliza para aliviar la ansiedad y control de la agitación causada por la abstinencia de alcohol. Método: se evaluó la variación de peso, friabilidad, dureza, tiempo de desintegración, cuantificación de principio activo, velocidad y perfil de disolución entre el medicamento innovador y medicamentos multifuentes comercializados en el mercado peruano, según lo establecido en la USP 42. Resultados: los resultados permitieron establecer que todas las tabletas multifuente de Diazepam 10 mg incluidos en esta investigación son bioequivalentes con la marca innovadora elegida y, por lo tanto, pueden ser intercambiables. Conclusiones: se estableció que las tabletas multifuentes de Diazepam 10 mg incluidos en esta investigación son bioequivalentes con el innovador y, por lo que permite proponer a la comunidad científica la determinación de la equivalencia farmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico. (AU)

Introduction: diazepam belongs to a group of medicines called benzodiazepines. These drugs are known to work in the brain through GABA and, it used to relieve anxiety and control the agitation caused by alcohol withdrawal. Method: variation in weight, friability, hardness, disintegration time, quantification of active ingredient, speed and dissolution profile between the innovative and multi-source drugs marketed in the Peruvian market. The evaluation of these presentations did with the USP 42 Pharmacopeia. Results: the results established that all Diazepam 10 mg multi-source tablets included in this research are bioequivalent with the chosen innovative brand and, therefore, can be interchangeable. Conclusions: The results observed that the multi-source tablets of Diazepam 10 mg included in this research are bioequivalent with the innovator and, therefore, allow the determination of pharmaceutical equivalence as a support element in the decision-making process for purchasing in the service pharmacist. (AU)

Calidad Biofarmacéutica e Intercambiabilidad de Medicamento / Biopharmaceutical Quality and Interchange of Drugs

Introducción: La industria farmacéutica que busca la aprobación para comercializar un medicamento genérico debe presentar datos que demuestren que la formulación genérica proporciona la misma calidad, eficacia y seguridad que el medicamento innovador. Por lo tanto, la mayoría de los medicamentos genéricos administrados por vía oral están aprobados en función de los resultados de uno o más estudios fisicoquímicos y biofarmacéuticos para demostrar bioequivalencia y posterior intercambiabilidad.Objetivo: Identificar en los artículos de investigación las posibles diferencias entre las pruebas fisicoquímicas y biofarmacéuticas de bioequivalencia de medicamentos genéricos con la de sus homólogos ya comercializados.Método: Se realizó la revisión de estudios de investigación originales, publicados desde enero del año 2003 hasta diciembre del 2019. Se consultaron 4 bases de datos Pubmed, ScienceDirect, Lilacs, Scielo. En inglés y español. Los descriptores utilizados fueron medicamento genérico, bioequivalencia, equivalencia terapéutica e intercambialidad, así mismo solo se seleccionaron aquellos artículos donde su forma farmacéutica de estudio fuese comprimidos.Resultados: Se seleccionaron en total 40 artículos para su evaluación, de los cuales 19 llegaron a la conclusión de bioequivalencia, otros 19 determinaron no bioequivalencia, para 1 no existía una conclusión definitiva, mientras que en 1 estudio que evaluaba a 3 medicamentos, la conclusión fue no bioequivalencia para 2 de ellos y para el tercero sí la había.Conclusión: La revisión revela que los estudios son insuficientes para indicar bioequivalencia entre los fármacos multifuentes (genéricos) y los innovadores, por lo que se necesita ampliar los estudios de bioequivalencia. (AU)

Introduction: The pharmaceutical industry seeking approval to market a generic drug must submit data demon-strating that the generic formulation provides the same quality, efficacy, and safety of the innovative drug. There-fore, most orally administered generic drugs are approved based on the results of one or more physicochemical and biopharmaceutical studies to demonstrate bioequivalence and subsequent interchangeability. Objective: Identify in research articles the possible differences between the physicochemical and biopharmaceuti-cal tests of bioequivalence of generic drugs with that of their corresponding innovative equivalents. Method: The original research studies, published from January 2003 to December 2019, were reviewed. 4 databases were consulted Pubmed, ScienceDirect, Lilacs, Scielo. In English and Spanish. The descriptors used were generic medicine, bioequivalence, therapeutic equivalence and interchangeability, likewise only those articles where their study pharmaceutical form was tablets were selected. Results: A total of 40 articles were selected for evaluation, of which 19 reached the conclusion of bioequivalence, another 19 determined non-bioequivalence, for 1 there was no definitive conclusion, while in a study that evaluated 3 drugs, the conclusion was no bioequivalence for 2 of them and bioequivalence for one. Conclusions: The review reveals that the studies are insufficient to indicate bioequivalence between multi-source (generic) and innovative drugs, so that bioequivalence studies need to be expanded. (AU)

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

La farmacia de los medicamentos genéricos / The pharmacy of generic drugs

RESUMEN Los medicamentos genéricos son una alternativa para mejorar el acceso a las medicinas que la población necesita y, además, hacen más sostenibles los programas de salud públicos y privados. Se ha seleccionado información y evidencia científica sobre este tipo de medicamentos de tal manera que los lectores -médicos, financiadores, organismos públicos y privados-puedan conformar su propia opinión y ayudar a tomar las decisiones más efectivas y eficientes. La relación existente entre los precios de estos productos y la protección de la propiedad intelectual a través de las patentes de los medicamentos es un centro de conflictos entre la industria farmacéutica y los sistemas de salud. En los Estados Unidos, la ley Hatch-Waxman ha cumplido una función muy importante al estimular el desarrollo de medicamentos genéricos. En un mismo intento, la Unión Europea (UE) ha desarrollado, a través de la Agencia Europea del Medicamento (EMA), una homogeneización en materia de autorización de medicamentos y exclusividad de los datos.

SUMMARY Generic medicines give the chance to improve access to medicaments that the population needs, and the possibility of making public and private health programs more sustainable. Information and scientific evidence on this type of medicines has been selected in such a way that the readers - doctors, financiers, public and private organizations - can shape their own opinion and help take the most effective and efficient decisions. The relationship between the prices of these products and the protection of intellectual property through patents for medicines is a center of conflicts between the Pharmaceutical Industry and health systems. In the United States, the Hatch-Waxman Act has played a very important role in stimulating the development of generic drugs. By his side, the European Union (EU) has developed, through the European Medicines Agency (EMA), a homogenization in terms of authorization of medicines and exclusivity of data.

Intercambialidade de produtos biológicos no Sistema Único de Saúde (SUS): principais desafios regulatórios / Interchangeability of biological products in the Brazilian Unified National Health System (SUS): the main regulatory challenges / Intercambiabilidad de productos biológicos en el Sistema Único de Salud (SUS): principales desafíos regulatorios

Resumo: Produtos biológicos revolucionaram a terapêutica mundial. O alto custo desses medicamentos, no entanto, ameaça a sustentabilidade dos sistemas de saúde. O desenvolvimento de cópias é tido como uma alternativa econômica, mas devido à complexidade desses produtos, muitos conceitos utilizados para os medicamentos genéricos não se aplicam. A intercambialidade entre produtos biológicos representa um desafio regulatório a ser superado. Este ensaio discute os principais desafios regulatórios relacionados ao estabelecimento de critérios para intercambialidade entre produtos biológicos novos e suas cópias no âmbito do Sistema Único de Saúde (SUS), considerando as diretrizes adotadas pelas principais agências reguladoras de medicamentos do mundo sobre a intercambialidade e o arcabouço regulatório vigente no Brasil para esta questão. Preocupações relacionadas à intercambialidade de produtos biológicos incluem substituição automática, nomenclatura, farmacovigilância, imunogenicidade e extrapolação das indicações terapêuticas e dos dados clínicos de produtos biológicos novos para suas cópias. Embora o sucesso clínico e os benefícios econômicos da alternância entre alguns produtos biológicos novos e seus biossimilares já tenham sido observados, a heterogeneidade das barreiras regulatórias para aprovação das cópias de produtos biológicos entre diferentes países deve ser considerada para a regulamentação da intercambialidade de produtos biológicos no Brasil.

Abstract: Biological products have sparked a worldwide therapeutic revolution. However, the high cost of these products threatens health systems' sustainability. The development of copies is considered an economic alternative, but due to the products' complexity, many concepts used in generic drugs do not apply. Interchangeability between biologicals poses a regulatory challenge. This essay discusses the main regulatory challenges for establishing criteria for interchangeability between new biologicals and their copies in the scope of the Brazilian Unified National Health System (SUS), considering the guidelines adopted by the world's main drug regulatory agencies concerning interchangeability and the prevailing Brazilian regulatory framework on this issue. Concerns related to the interchangeability of biologicals include automatic substitution, nomenclature, pharmacovigilance, immunogenicity, and extrapolation of therapeutic indications and clinical data from new biologicals to their copies. While the clinical success and economic benefits of switching from new biologicals to their biosimilars have already been observed, the heterogeneity between countries in the regulatory barriers to the approval of copies of biologicals should be taken into consideration during the regulation of interchangeability of biologicals in Brazil.

Resumen: Los productos biológicos revolucionaron la terapéutica mundial. El alto coste de estos medicamentos, no obstante, amenaza la sostenibilidad de los sistemas de salud. El desarrollo de copias se considera como una alternativa económica, pero debido a la complejidad de estos productos, muchos conceptos utilizados para los medicamentos genéricos no se aplican a los mismos. La intercambiabilidad entre productos biológicos representa un desafío regulatorio que se debe superar. Este trabajo discute los principales desafíos regulatorios, relacionados con el establecimiento de criterios para la intercambiabilidad entre productos biológicos nuevos y sus copias en el ámbito del Sistema Único de Salud (SUS), considerando las directrices adoptadas por las principales agencias regulatorias de medicamentos del mundo sobre la intercambiabilidad y el armazón regulatorio vigente en Brasil para esta cuestión. Las preocupaciones relacionadas con la intercambiabilidad de productos biológicos incluyen la sustitución automática, nomenclatura, farmacovigilancia, inmunogenicidad y extrapolación de las indicaciones terapéuticas, así como de los datos clínicos de productos biológicos nuevos para sus copias. A pesar de que el éxito clínico y los beneficios económicos de la alternancia entre algunos productos biológicos nuevos y sus biosimilares, ya se han observados, la heterogeneidad de las barreras regulatorias para la aprobación de las copias de productos biológicos entre los diferentes países debe ser considerada para la regulación de la intercambiabilidad de productos biológicos en Brasil.

Evaluación de la intercambiabilidad in vitro de diferentes marcas de tabletas de diclofenaco sódico disponibles en el mercado colombiano / In vitro evaluation of the interchangeability of different brands of diclofenac sodium tablets available in the Colombian market

Introducción. El diclofenaco sódico se clasifica como un antiinflamatorio no esteroide. Dado que es de venta libre, el paciente no tiene ningún seguimiento por parte de los equipos de salud, y como sus fuentes son múltiples, es necesario establecer la equivalencia entre ellas en estudios in vitro, que son los más prácticos y plantean un menor compromiso ético. Objetivos. Determinar la intercambiabilidad de diferentes marcas comerciales de diclofenaco sódico comparadas con el producto innovador mediante un estudio in vitro de tabletas comerciales de 50 mg, según los lineamientos del Sistema de Clasificación Biofarmacéutica (SCB). Materiales y métodos. Se desarrollaron pruebas físicas y químicas siguiendo las indicaciones de laedición 39 de la United States Pharmacopeia (USP). Para la cuantificación, se validó una metodología analítica según lo establecido en la mencionada farmacopea y la guía Q2 del International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Los perfiles de disolución y sus análisis se rigieron por lo establecido por la Organización Mundial de la Salud y las normas nacionales. Resultados. Todos los productos aprobaron las pruebas físicas. En cuanto a la disolución, la etapa ácida también fue superada por todas las marcas, pero una marca falló en la etapa alcalina. El análisis de similitud reveló que solo un producto fue equivalente al innovador y tres fueron supradisponibles, aunque dichas marcas también podrían considerarse equivalentes al producto innovador. Conclusiones. De las ocho marcas evaluadas, tres no cumplieron totalmente con la prueba de valoración del principio activo y del porcentaje de disolución; solo una marca fue intercambiable con el producto innovador y tres fueron supradisponibles comparadas con este, por lo cual no constituyen un riesgo para el paciente.

Introduction: Diclofenac sodium is classified as a non-steroidal anti-inflammatory drug. As diclofenac is an over-the-counter drug, its use among patients cannot be monitored by health teams in follow-up sessions. Given the multiple sources of diclofenac sodium, their interchangeability must be investigated, particularly in the form of in vitro studies, which are the most practical research type and entail minimal ethical commitment. Objectives: To determine the interchangeability of the different commercial brands of diclofenac sodium relative to the innovative product, this work carries out an in vitro study of eight commercial products of diclofenac sodium (50 mg) following the guidelines of the Biopharmaceutical Classification System. Materials and methods: Physical and chemical tests were developed following the guidelines of the 39th edition of the United States Pharmacopoeia. An analytical methodology was validated for the quantification of diclofenac according to the current pharmacopoeia and the Q2 guideline ofthe International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Dissolution profiles and their analyseswere governed by the regulations established by the World Health Organization and the national regulations. Results: All the products passed the physical tests. In the dissolution assays, the acid stage was overcome by all brands, but in the alkaline stage, one brand failed. The analysis of the similarities revealed that only one product was equivalent to the innovator and that three were supra-available, although these brands could also be considered equivalent to the innovator. Conclusions: Of the eight brands evaluated, three failed the test forthe active principle and the percentage of dissolution. Only one brand was found to be interchangeable with the innovator, and three were identified to besupra-availableand, thus, they do not present a risk for patients.

Switching from an originator anti-TNF to a biosimilar in patients with inflammatory bowel disease: Can it be recommended? A systematic review.

AIM: To review the effectiveness and safety of switching from an originator anti-TNF (Remicade®) to a biosimilar (CT-P13) in patients with inflammatory bowel disease (IBD). METHODS: Electronic and manual search up to September 2017. RESULTS: We identified 24 studies evaluating switching between Remicade® and CT-P13 in 1326 patients. Disease control (no worsening after switching) was confirmed in most of the patients (weighted mean, 88%; 95% CI=86-89%). No unexpected adverse effects were reported in any of the studies. CONCLUSION: The risks of switching from Remicade® to a biosimilar seem to be purely theoretical and are not supported by the (still limited) real-world clinical practice experience. On the contrary, a steadily increasing number of publications have shown that there seem to be no safety or efficacy concerns about switching. Therefore, switching from originator to biosimilar infliximab in patients with IBD may be considered acceptable.

Update on biosimilars in inflammatory bowel disease: Position and recommendations in Mexico. / Actualización sobre los medicamentos biocomparables en la enfermedad inflamatoria intestinal: posición y recomendación en México.

The biotechnology-derived medicines known as biosimilars are defined as non-originator treatments that have demonstrated quality, efficacy, and safety comparable to the reference biologic drug. Clinical trials have shown that the infliximab biosimilar, CT-P13, and the candidates for the adalimumab biosimilars, ABP 501 and ZRC 3197, are not significantly different, with respect to efficacy and safety, from the originator drugs in patients with other autoimmune diseases. However, controversy has arisen over the use of biosimilars in inflammatory bowel disease, due to the incipient evidence not only in patients with no previous biotechnology treatment, but also in patients in remission, that could be switched to a biosimilar for non-medical reasons. The present review is the first critical analysis by different specialists in the area of gastroenterology on the use of biosimilars in inflammatory bowel disease, the evidence on interchangeability, the extrapolation of indications, efficacy, safety, immunogenicity, and the clinical impact of the Mexican health regulations. The aim of our review was to make the positioning and recommendations of these new therapeutic options known, given that they have a potential cost-benefit for both patients and healthcare institutions.

Current state of biosimilars in Mexico: The position of the Mexican College of Rheumatology, 2016. / Escenario actual de los medicamentos biocomparables en México: posicionamiento del Colegio Mexicano de Reumatología, 2016.

The present document is a position statement of the Mexican College of Rheumatology on the use of biosimilars in rheumatic diseases. This position considers that biosimilars should be considered as interchangeable, that automatic substitution without previous notice in stable patients during follow-up is not ethical, that the approval of a biosimilar should only be given after exhaustive review of preclinical and clinical data marked by Mexican regulations, that it should be clearly stated in the nomenclature of biologic drugs which is the innovator and which is the biosimilar, that it is not correct to choose a biosimilar as treatment based only on economic reasons or extrapolate indications based only on the approval of the innovator and in the absence of safety and efficacy data for the biosimilar.

Accuracy of Cirrus HD-OCT and Topcon SP-3000P for measuring central corneal thickness.

PURPOSE: To compare and analyze the interchangeability of three measuring systems, each based on a different technique, for central corneal thickness (CCT) analysis. METHODS: CCT measurements were measured using optical coherence tomography (OCT), non-contact specular microscopy (NCSM), and ultrasonic pachymetry (USP) in 60 eyes of 60 healthy patients with a mean age of 66.5±15.0 years and a mean spherical equivalent of 0.43±1.14 D. Analysis of variations in measurement concordance and correlation among the three different methods were performed. Comparison of CCT measurements were done using Bland-Altman plots (with bias and 95% confidence intervals), intraclass correlation coefficient (ICC), and paired t-student analysis. RESULTS: Mean CCT values were: 549.20±26.91µm for USP (range 503-618µm), 514.20±27.49µm for NCSM (range 456-586µm) and 542.80±25.56µm for OCT (range 486-605µm). CCT values obtained with NCMS were significantly lower than those obtained with OCT and USP methods. NCMS CCT value was 36.08±10.72µm lower than USP value (p<0.05), and NCMS CCT value was 7.88±8.86µm lower than OCT value (p<0.05). ICC between USP-NCSM pair was 0.488 and 0.909 between USP-OCT pair. CONCLUSION: OCT and UPS offered highly comparable results, whereas NCSM offered lower mean CCT values compared to the other two methods. Therefore, NCSM should not be considered a reliable method for measuring CCT and should rather be considered for assessing longitudinal changes in the same patient.

In vitro evaluation of the interchangeability of different brands of diclofenac sodium tablets available in the Colombian market / Evaluación de la intercambiabilidad in vitro de diferentes marcas de tabletas de diclofenaco sódico disponibles en el mercado colombiano

Introduction: Diclofenac sodium is classified as a non-steroidal anti-inflammatory drug. As diclofenac is an over-the-counter drug, its use among patients cannot be monitored by health teams in follow-up sessions. Given the multiple sources of diclofenac sodium, their interchangeability must be investigated, particularly in the form of in vitro studies, which are the most practical research type and entail minimal ethical commitment. Objectives: To determine the interchangeability of the different commercial brands of diclofenac sodium relative to the innovative product, this work carries out an in vitro study of eight commercial products of diclofenac sodium (50 mg) following the guidelines of the Biopharmaceutical Classification System. Materials and methods: Physical and chemical tests were developed following the guidelines of the 39th edition of the United States Pharmacopoeia. An analytical methodology was validated for the quantification of diclofenac according to the current pharmacopoeia and the Q2 guideline ofthe International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Dissolution profiles and their analyseswere governed by the regulations established by the World Health Organization and the national regulations. Results: All the products passed the physical tests. In the dissolution assays, the acid stage was overcome by all brands, but in the alkaline stage, one brand failed. The analysis of the similarities revealed that only one product was equivalent to the innovator and that three were supra-available, although these brands could also be considered equivalent to the innovator. Conclusions: Of the eight brands evaluated, three failed the test forthe active principle and the percentage of dissolution. Only one brand was found to be interchangeable with the innovator, and three were identified to besupra-availableand, thus, they do not present a risk for patients.

Introducción. El diclofenaco sódico se clasifica como un antiinflamatorio no esteroide. Dado que es de venta libre, el paciente no tiene ningún seguimiento por parte de los equipos de salud, y como sus fuentes son múltiples, es necesario establecer la equivalencia entre ellas en estudios in vitro, que son los más prácticos y plantean un menor compromiso ético.Objetivos. Determinar la intercambiabilidad de diferentes marcas comerciales de diclofenaco sódico comparadas con el producto innovador mediante un estudio in vitro de tabletas comerciales de 50 mg, según los lineamientos del Sistema de Clasificación Biofarmacéutica (SCB).Materiales y métodos. Se desarrollaron pruebas físicas y químicas siguiendo las indicaciones de la edición 39 de la United States Pharmacopeia (USP). Para la cuantificación, se validó una metodología analítica según lo establecido en la mencionada farmacopea y la guía Q2 del International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Los perfiles de disolución y sus análisis se rigieron por lo establecido por la Organización Mundial de la Salud y las normas nacionales.Resultados. Todos los productos aprobaron las pruebas físicas. En cuanto a la disolución, la etapa ácida también fue superada por todas las marcas, pero una marca falló en la etapa alcalina. El análisis de similitud reveló que solo un producto fue equivalente al innovador y tres fueron supradisponibles, aunque dichas marcas también podrían considerarse equivalentes al producto innovador.Conclusiones. De las ocho marcas evaluadas, tres no cumplieron totalmente con la prueba de valoración del principio activo y del porcentaje de disolución; solo una marca fue intercambiable con el producto innovador y tres fueron supradisponibles comparadas con este, por lo cual no constituyen un riesgo para el paciente.

El papel de los biosimilares en la enfermedad inflamatoria intestinal: una realidad en nuestro país / The Role of Biosimilars in Inflammatory Bowel Disease: A Reality in our Country

Resumen La enfermedad inflamatoria intestinal (EII) es un término con el que se conocen varias entidades, las 2 más importantes son: la colitis ulcerativa idiopática (CUI) y la enfermedad de Crohn (EC), cuyo origen es multifactorial y se caracterizan por un fenómeno inflamatorio, crónico, recurrente con diferentes grados de severidad del tubo digestivo; pero además con afectación potencial de otros órganos. En la última década ha habido un renovado interés en dichas entidades, debido a una incidencia creciente de estas, pero también debido al desarrollo de medicamentos que por primera vez están cambiando la historia natural de estas enfermedades: son los medicamentos llamados biológicos, que son aquellos producidos o derivados de organismos vivos y representan el sector de mayor crecimiento en la industria farmacéutica mundial. Debido al interés comercial, se han desarrollado y sometido a las autoridades reguladoras productos no originadores; similares, pero no idénticos a los productos de referencia. La Agencia Europea de Medicamentos (EMA) aprobó el primer biosimilar del infliximab para todas las indicaciones en las cuales este estaba aprobado, incluidas: colitis ulcerativa moderada a severa en todas las edades, EC moderada a severa en todas las edades, al igual que EC fistulizante, artritis psoriásica (AP), psoriasis, espondilitis anquilosante (EA) y artritis reumatoide (AR) (1). En esta revisión nos proponemos definir lo que son estos productos al igual que algunos conceptos relacionados (extrapolación, sustitución e intercambiabilidad), además hacer una revisión histórica de su desarrollo, sus indicaciones actuales, las posiciones de las diferentes asociaciones científicas al respecto y, lo más importante, brindar datos de la vida real en cuanto a su efectividad, seguridad y costos en los diferentes países donde se han estado usando.

Abstract The term Inflammatory Bowel Disease (IBD) is used to identify several entities, the two most important of which are Idiopathic Ulcerative Colitis (IUC) and Crohn's Disease (EC). Both are multifactorial in origin, are chronic and recurrent, are characterized by inflammation, have varying degrees of severity, and potentially involve other organs. In the last decade there has been renewed interest in these entities due to growing incidence and to the development of drugs called biologicals. For the first time, these drugs have changed the natural history of these diseases. They are produced or derived from living organisms and represent the fastest growing sector in the global pharmaceutical industry. Due to commercial interest, products similar but not identical to the original products have been developed and submitted to regulatory authorities. The European Medicines Agency has approved the first biosimilar for infliximab for all indications for which it has been approved. These include moderate to severe ulcerative colitis (UC) at all ages, moderate to severe Crohn's disease (CD) at all ages, fistulizing Crohn's disease, Psoriasic arthritis, Psoriasis, Ankylosing Spondylitis, and Rheumatoid Arthritis. 1 In this review, we define what these products are, as well as some concepts coined for their usage including extrapolation, substitution and interchangeability. We also make a historical review of their development, current indications, the positions of various scientific associations with respect to them, and - most importantly - provide real-life data regarding their effectiveness, safety and costs in countries where they have been used.

[Comparability study of analytical results between a group of clinical laboratories]. / Intercambiabilidad de resultados entre los diferentes laboratorios clínicos Catlab.

OBJECTIVE: To describe the study of the comparability of the measurements levels of biological tests processed in biochemistry in Catlab's 4 laboratories. MATERIAL AND METHODS: Quality requirements, coefficients of variation and total error (CV% and TE %) were established. Controls were verified with the precision requirements (CV%) in each test and each individual laboratory analyser. Fresh serum samples were used for the comparability study. The differences were analysed using a Microsoft Access® application that produces modified Bland-Altman plots. RESULTS: The comparison of 32 biological parameters that are performed in more than one laboratory and/or analyser generated 306 Bland-Altman graphs. Of these, 101 (33.1%) fell within the accepted range of values based on biological variability, and 205 (66.9%) required revision. Data were re-analysed based on consensus minimum specifications for analytical quality (consensus of the Asociación Española de Farmacéuticos Analistas (AEFA), the Sociedad Española de Bioquímica Clínica y Patología Molecular (SEQC), the Asociación Española de Biopatología Médica (AEBM) and the Sociedad Española de Hematología y Hemoterapia (SEHH), October 2013). With the new specifications, 170 comparisons (56%) fitted the requirements and 136 (44%) required additional review. Taking into account the number of points that exceeded the requirement, random errors, range of results in which discrepancies were detected, and range of clinical decision, it was shown that the 44% that required review were acceptable, and the 32 tests were comparable in all laboratories and analysers. CONCLUSIONS: The analysis of the results showed that the consensus requirements of the 4 scientific societies were met. However, each laboratory should aim to meet stricter criteria for total error.

Biosimilars in Dermatology: Current Situation (Part II).

The first biosimilar version of a biologic agent used to treat psoriasis (infliximab) entered the Spanish market on February 16 of this year, and more biosimilars can be expected to follow in the coming months and years. Logically, this new situation will have economic repercussions and alter prescribing patterns among dermatologists. In this second part of the review, we will look at several somewhat contentious issues, such as the extrapolation of indications, interchangeability, and automatic substitution. We will also review the biosimilars with indications for psoriasis currently in the clinical development pipeline and assess their potential to offer comparable efficacy and safety to the reference product while contributing to the sustainability of the public health care system.

Biosimilars in Dermatology: Current Situation (Part I).

The first biosimilar version of a biologic agent used to treat psoriasis (infliximab) entered the Spanish market on February 16 of this year, and more biosimilars can be expected to follow in the coming months and years. Logically, this new situation will have economic repercussions and alter prescribing patterns among dermatologists. In this article, we review regulatory issues related to the approval of biosimilars, with a particular focus on the situation in the European Union. We will examine analytical characterization studies and special considerations for clinical trials with biosimilars, and also look at several somewhat contentious issues, such as the extrapolation of indications, interchangeability, and automatic substitution. Finally, we will review the biosimilars with indications for psoriasis currently in the clinical development pipeline and assess their potential to offer comparable efficacy and safety to the reference product while contributing to the sustainability of the public health care system.

Comparación de la biodisponibilidad y la farmacocinética entre dos formulaciones de tabletas de metforminade 850 mg en voluntarios colombianos sanos / Bioavalaibility and pharmacokinetic comparison of two formulations of metformin 850 mg tablets in healthy Colombian volunteers

Purpose: The aim of this study was to compare the bioavailability of two formulations of metformin 850 mg tablets: Glucophage® from Merck Santè laboratories (reference product) and Metformin from Winthrop Pharmaceuticals de Colombia SA (test product) in healthy Colombian volunteers.Methods: A random, double blind, two-period, two-week wash out period, crossover study was performed in 24 healthy male and female volunteers for a single 850-mg dose of metformin tablets administrated with 240 ml of water after 12 hours of fasting. Once the drug was administrated, blood samples were collected before and within 24 hour, and plasma metformin concentration was determined by using a validated HPLC method. Pharmacokinetic parameters such as Cmax, AUC0-96h, AUC0-∞, and Tmax were determined. The formulations were considered bioequivalent if the logarithmic mean ratios of ln-transformed Cmax and AUC0-∞ values were within the equivalence range of 80%-125%.Results: ANOVA analysis of the ln-transformed Cmax and AUC0-∞ indicated that none of the effects examined (formulation, period, within and between-subjet variances and carry over) was statistically significant. The mean (±SD) of Cmax 1217.38 (± 251.72) ng/ml vs. 1305.25 (± 301.06) ng/ml, AUC0-96h 1363.49 (± 315.51) ng.h/ml vs. 1584.82 (± 368.75) ng.h/ml, AUC0-∞, 7155.75 (± 1440.74) ng.h/ml vs. 7777.08 (± 1896.49) ng.h/ml, and Tmax 2.57 (± 0.93) h vs. 2.22 (± 0.94) h were obtained with test and reference formulations, respectively. These pharmacokinetic parameters presented differences with the results from other published papers. The 90% confidence interval of the logarithmic ratio of AUC0-∞ and Cmax was within the range of 80-125%.Conclusions: In this study in healthy Colombian volunteers, a single 850-mg dose of metformin tablet test formulation met the criteria for bioequivalence to the reference formulation based on pharmacokinetic parameters AUC0-∞ and Cmax.

Objetivo: El objetivo de este estudio es comparar la bioequivalencia de dos formulaciones de tabletas de metformina de 850 mg: Glucophage® del Laboratorio Merck Santè (producto de referencia) y metformina de Laboratorios Winthrop Pharmaceuticals de Colombia SA (producto de prueba), en voluntarios colombianos sanos.Métodos: Se realizó un estudio aleatorizado, doble ciego, cruzado, en dos períodos y con un tiempo de lavado de dos semanas, en 24 voluntarios sanos, hombres y mujeres, que recibieron una dosis única de metformina de 850 mg, con 240 ml de agua, después de 12 horas de ayuno. Luego de la administración del medicamento, se recolectaron muestras de sangre durante 24 horas y las concentraciones plasmáticas de metformina se determinaron con un método de HPLC validado. Se calcularon los parámetros farmacocinéticos: Cmax, AUC0-96h, AUC0-∞, y Tmax. Las formulaciones se consideraron bioequivalentes si la relación de la media transformada a ln de Cmax y AUC0-∞ estaba dentro del rango de bioequivalencia de 80% a 125%.Resultados: El Anova de los datos transformados a ln de Cmax y AUC0-∞ indicaron que ninguno de los efectos analizados (formulación, período, variación intra e intersujetos y arrastre) fueron estadísticamente significativos. La media (±SD) de los parámetros obtenidos para los productos de prueba y de referencia, respectivamente, fueron: Cmax 1217.38 (± 251.72) ng/ml vs. 1305.25 (± 301.06) ng/ml, AUC0-96h 1363.49 (± 315.51) ng.h/ml vs. 1584.82 (± 368.75) ng.h/ml, AUC0-∞, 7155.75 (± 1440.74) ng.h/ml vs. 7777.08 (± 1896.49) ng.h/ml, and Tmax 2.57 (± 0.93) h vs. 2.22 (± 0.94) h. El intervalo de confianza de la relación logarítmica del AUC0∞ y Cmax se encontró dentro del rango de 80% a 125%.

Estudios de bioexención (in vitro) para establecer equivalencia de medicamentos / Biowaiver studies (in vitro) to establish equivalence of drugs

En el presente trabajo se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de medicamentos similares con respecto a los innovadores, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de bioexención in vitro para determinar la intercambiabilidad de aquellos medicamentos similares provenientes de diferentes fuentes que se han liberado de los estudios de bioequivalencia (in vivo). Además, se presentan algunos resultados de estudios de test de disolución para dar a conocer la metodología usada en la bioexención y se detallan los requisitos para aprobar un Centro de Bioequivalencia in vitro.

In this review, the concepts, guidelines and proposals regarding the determination of therapeutic equivalence of similar drug products are analyzed from a national and international point of view. The scientific background of the in vitro biowaiver studies that may result in the interchange ability of multisource drug product that have been waived from the demonstration of in vivo bioequivalence studies is also explained. In order to explain the methods in biowaiver studies, results of dissolution kinetics are shown as well as the requirements to approve an in vitro biopharmaceutic center.