Biosimilars approvals by thirteen regulatory authorities: A cross-national comparison.

Biosimilars are biological medicines highly similar to a previously licensed reference product and their licensing is expected to improve access to biological therapies. This study aims to present an overview of biosimilars approval by thirteen regulatory authorities (RA). The study is a cross-national comparison of regulatory decisions involving biosimilars in Argentina, Australia, Brazil, Chile, Canada, Colombia, Europe, Hungary, Guatemala, Italy, Mexico, Peru and United States. We examined publicly available documents containing information regarding the approval of biosimilars and investigated the publication of public assessment reports for registration applications, guidelines for biosimilars licensing, and products approved. Data extraction was conducted by a network of researchers and regulatory experts. All the RA had issued guidance documents establishing the requirements for the licensing of biosimilars. However, only three RA had published public assessment reports for registration applications. In total, the investigated jurisdictions had from 19 to 78 biosimilars approved, most of them licensed from 2018 to 2020. In spite of the advance in the number of products in recent years, some challenges still persist. Limited access to information regarding the assessment of biosimilars by RA can affect confidence, which may ultimately impact adoption of these products in practice.

Comparative analysis of the use and control of thalidomide in Brazil and different countries: is it possible to say there is safety?

INTRODUCTION: One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED: This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION: This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.

Regulatory reliance pathways during health emergencies: enabling timely authorizations for COVID-19 vaccines in Latin America / Mecanismos de utilización de las decisiones de autoridades regulatorias de otras jurisdicciones en las emergencias de salud: autorización oportuna de las vacunas contra la COVID-19 en América Latina / Uso de decisões regulatórias de outras autoridades durante emergências sanitárias e a tempestividade da autorização de vacinas contra a COVID-19 na América Latina

ABSTRACT Objectives. To map the timing and nature of regulatory reliance pathways used to authorize COVID-19 vaccines in Latin America. Methods. An observational study was conducted assessing the characteristics of all COVID-19 vaccine authorizations in Latin America. For every authorization it was determined whether reliance was used in the authorization process. Subgroups of reference national regulatory authorities (NRAs) and non-reference NRAs were compared. Results. 56 authorizations of 10 different COVID-19 vaccines were identified in 18 countries, of which 25 (44.6%) used reliance and 12 (21.4%) did not. For the remaining 19 (33.0%) it was not possible to determine whether reliance was used. Reference agencies used reliance less often (40% of authorizations with a known pathway) compared to non-reference agencies (100%). The median review time was just 15 days and does not meaningfully differ between reliance and non-reliance authorizations. Conclusions. This study demonstrated that for these vaccines, despite reliance pathways being associated with numerous rapid authorizations, independent authorization review times were not considerably longer than reliance reviews; reliance pathways were not a prerequisite for rapid authorization. Nevertheless, reliance pathways provided rapid authorizations in response to the COVID-19 emergency.

RESUMEN Objetivos. Determinar dónde y cuándo se usaron las decisiones de autoridades regulatorias de otras jurisdicciones y la naturaleza de estos mecanismos para autorizar vacunas contra la COVID-19 en América Latina. Métodos. Se realizó un estudio observacional para evaluar las características de todas las autorizaciones de vacunas contra la COVID-19 en América Latina. Para cada autorización se determinó si se emplearon las decisiones de autoridades regulatorias de otras jurisdicciones en el proceso de autorización. Se compararon subgrupos de autoridades regulatorias nacionales (ARN) consideradas de referencia con otras ARN no usadas como referencia. Resultados. Se determinó dónde se otorgaron 56 autorizaciones de 10 vacunas diferentes contra la COVID-19 en 18 países; de estas 56 autorizaciones, 25 (44,6%) hicieron uso de las decisiones de autoridades regulatorias de otras jurisdicciones y 12 (21,4%), no. Para las 19 restantes (33,0%) no fue posible determinar si se hizo uso de las decisiones de autoridades regulatorias de otras jurisdicciones. Los organismos de referencia utilizaron las decisiones de autoridades regulatorias de otras jurisdicciones con menos frecuencia (40% de las autorizaciones con un mecanismo conocido) en comparación con los organismos no usados como referencia (100%). El plazo medio de revisión fue de tan solo 15 días y no difiere significativamente entre las autorizaciones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones y las que no las emplearon. Conclusiones. En este estudio se demostró que, a pesar de que los mecanismos de utilización de las decisiones de autoridades regulatorias de otras jurisdicciones se asocian en muchos casos con autorizaciones rápidas, para estas vacunas los plazos de revisión independiente para la autorización no fueron considerablemente mayores que los de las revisiones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones. También se demostró que para obtener una autorización rápida no se requería la utilización de las decisiones de autoridades regulatorias de otras jurisdicciones. Sin embargo, estos mecanismos proporcionaron autorizaciones rápidas en respuesta a la emergencia por la COVID-19.

RESUMO Objetivos. Mapear a tempestividade e a natureza do uso de decisões regulatórias de outras autoridades (reliance regulatório) para autorização de vacinas contra a COVID-19 na América Latina. Métodos. Em um estudo observacional, foram avaliadas as características de todas as autorizações de vacinas contra COVID-19 na América Latina. Para cada autorização, foi determinado se foram utilizadas decisões de outras autoridades regulatórias para embasar o processo de autorização. Foram comparados subgrupos de autoridades reguladoras nacionais (ARN) de referência (ARNr) e ARN não consideradas de referência. Resultados. Foram identificadas 56 autorizações de 10 vacinas diferentes contra a COVID-19 em 18 países, das quais 25 (44,6%) utilizaram decisões de outras ARN como base para o registro e 12 (21,4%) não. Para as 19 (33,0%) autorizações restantes, não foi possível determinar se decisões de outras ARN foram utilizadas. As ARNr utilizaram decisões de outras autoridades com menos frequência (40% das autorizações com via regulatória conhecida) em comparação com as ARN não consideradas de referência (100%). A mediana do tempo de tramitação foi de apenas 15 dias, sem diferença significativa entre processos nos quais foram utilizadas decisões de outras agências e processos que não as utilizaram. Conclusões. Este estudo demonstrou que, para estas vacinas, apesar de o uso do reliance regulatório estar associado a várias autorizações rápidas, os tempos de tramitação não foram consideravelmente maiores em autorizações independentes do que quando foram utilizadas decisões de outras ARN; o reliance regulatório não foi um pré-requisito para autorização rápida. No entanto, o uso de tais processos viabilizou autorizações rápidas em resposta à emergência de COVID-19.

[Comparative assessment of off-label and unlicensed drug prescription in neonatal intensive care: FDA versus Brazilian guidelines]. / Evaluación comparativa de la prescripción off-label y unlicensed de fármacos en cuidados intensivos neonatales: Guías de la FDA versus guías brasileñas.

INTRODUCTION: Regulatory agencies are responsible for defining the use of off-label (OL) and unlicensed (UL) drug prescription in neonatal intensive care. However, these regulatory criteria may differ between agencies in different countries. The aim of this study was to establish the frequency of OL and UL drug prescription in a sample of patients in a neonatal intensive care unit applying the criteria of the Food and Drug Administration (FDA) of the United States and the Agência Nacional de Vigilância Sanitária (ANVISA) of Brazil, analysing the differences observed in the results based on the applied criteria. METHODS: Prospective cohort study in neonates admitted for more than 24hours to the neonatal intensive care unit (NICU) of a teaching maternity hospital between August 2017 and July 2018. We obtained information concerning the drugs included in the analysis of OL and UL prescriptions from the DrugDex-Micromedex® and official information on pharmaceutical products in Brazil. We used the kappa correlation coefficient to assess the agreement between the FDA and ANVISA criteria. We defined disagreement as a kappa value of less than 0.200. RESULTS: We evaluated 220 neonates admitted to the NICU and 17,421 items prescribed during the study period. We did not find a difference in the proportion of neonates in which at least 1 drug was prescribed under OL conditions applying the FDA versus the ANVISA criteria (96.4% vs. 98.6%). We found differences between the FDA and ANVISA in the OL classification based on the authorised age of use and indications for prescription, mainly in systemic antimicrobials and cardiovascular drugs. When we compared the prescribing information provided by the FDA and the ANVISA, we found that the criteria of the ANVISA were less specific. CONCLUSIONS: OL and UL drug prescription are frequent in neonatal intensive care applying the criteria of either agency, although the FDA has established more detailed criteria in terms of the ages and indications for which prescription is authorised.

Regulatory reliance to approve new medicinal products in Latin American and Caribbean countries / Utilización de decisiones de autoridades regulatorias de otras jurisdicciones para aprobar nuevos productos medicinales en países de América Latina y el Caribe / Uso de decisões regulatórias de outras jurisdições para aprovação de novas especialidades farmacêuticas em países da América Latina e Caribe

ABSTRACT Objective. To describe the current status of regulatory reliance in Latin America and the Caribbean (LAC) by assessing the countries' regulatory frameworks to approve new medicines, and to ascertain, for each country, which foreign regulators are considered as trusted regulatory authorities to rely on. Methods. Websites from LAC regulators were searched to identify the official regulations to approve new drugs. Data collection was carried out in December 2019 and completed in June 2020 for the Caribbean countries. Two independent teams collected information regarding direct recognition or abbreviated processes to approve new drugs and the reference (trusted) regulators defined as such by the corresponding national legislation. Results. Regulatory documents regarding marketing authorization were found in 20 LAC regulators' websites, covering 34 countries. Seven countries do not accept reliance on foreign regulators. Thirteen regulatory authorities (Argentina, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Mexico, Panama, Paraguay, Peru, Uruguay, and the unique Caribbean Regulatory System for 15 Caribbean States) explicitly accept relying on marketing authorizations issued by the European Medicines Agency, United States Food and Drug Administration, and Health Canada. Ten countries rely also on marketing authorizations from Australia, Japan, and Switzerland. Argentina, Brazil, Chile, and Mexico are reference authorities for eight LAC regulators. Conclusions. Regulatory reliance has become a common practice in the LAC region. Thirteen out of 20 regulators directly recognize or abbreviate the marketing authorization process in case of earlier approval by a regulator from another jurisdiction. The regulators most relied upon are the European Medicines Agency, United States Food and Drug Administration, and Health Canada.

RESUMEN Objetivo. Describir el estado actual de la utilización de las decisiones de autoridades regulatorias de otras jurisdicciones en América Latina y el Caribe mediante la evaluación de los marcos regulatorios nacionales para la aprobación de nuevos medicamentos y establecer los organismos regulatorios extranjeros que se consideran autoridades regulatorias confiables para cada país. Métodos. Se realizaron búsquedas en los sitios web de las autoridades regulatorias de América Latina y el Caribe para identificar las regulaciones oficiales para la aprobación de nuevos medicamentos. La recopilación de datos se llevó a cabo en diciembre del 2019 y se completó en junio del 2020 para los países del Caribe. Dos equipos independientes recopilaron información sobre el reconocimiento directo o los procedimientos abreviados para la aprobación de nuevos medicamentos y los autoridades regulatorias de referencia (confiables) así definidos en la legislación nacional correspondiente. Resultados. Se encontraron documentos regulatorios sobre la aprobación de nuevos productos en los sitios web de veinte organismos regulatorios de América Latina y el Caribe, que abarcaban 34 países. Siete países no aceptan la utilización de decisiones de autoridades regulatorias extranjeras. Trece autoridades regulatorias (Argentina, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, México, Panamá, Paraguay, Perú, República Dominicana, Uruguay y el sistema regulador único para quince Estados del Caribe) aceptan de manera explícita confiar las decisiones para aprobación de nuevos medicamentos emitidas por la Agencia Europea de Medicamentos, la Administración de Alimentos y Medicamentos de Estados Unidos y Salud Canadá. Diez países aceptan también utilizar las autorizaciones para la comercialización de Australia, Japón y Suiza. Argentina, Brasil, Chile y México son autoridades de referencia para ocho autoridades regulatorias en la región. Conclusiones. La utilización de las decisiones de autoridades regulatorias de otras jurisdicciones se han convertido en una práctica común en América Latina y el Caribe. Trece de veinte autoridades regulatorias reconocen directamente o abrevian el proceso de aprobación de nuevos medicamentos en caso de que hayan recibido previamente la aprobación por parte de un organismo regulatorio de otra jurisdicción. La Agencia Europea de Medicamentos, la Administración de Alimentos y Medicamentos de Estados Unidos y Salud Canadá son las autoridades regulatorias de otras jurisdicciones en las cuales los reguladores de América Latina y el Caribe confían más.

RESUMO Objetivo. Descrever a prática atual de uso de decisões regulatórias de outras jurisdições na América Latina e no Caribe (ALC) mediante avaliação os marcos regulatórios dos países para aprovação de novos medicamentos e verificar, para cada país, quais entidades reguladoras estrangeiras são consideradas autoridades reguladoras de confiança por cada país. Métodos. Foi realizada uma pesquisa nos sites das autoridades reguladoras da ALC para identificar as regulamentações oficiais para aprovação de novos medicamentos. A coleta de dados foi feita em dezembro de 2019 e concluída em junho de 2020 para os países do Caribe. Dois grupos independentes coletaram informações sobre o reconhecimento direto ou o procedimento abreviado para aprovação de novos medicamentos e as autoridades reguladoras de referência (de confiança) definidas como tal pela respectiva legislação nacional. Resultados. Documentos regulatórios relacionados à aprovação de novos produtos foram obtidos de 20 sites de órgãos reguladores da ALC, abrangendo 34 países. Sete países não admitem o uso de decisões regulatórias de entidades reguladoras externas. Treze autoridades reguladoras (na Argentina, Colômbia, Costa Rica, El Salvador, Equador, Guatemala, México, Panamá, Paraguai, Peru, República Dominicana, Uruguai e o Sistema Regulador do Caribe unificado para 15 Estados caribenhos) admitem explicitamente a admissibilidade de decisões regulatórias para aprovação de novos medicamentos de outras jurisdições, quais sejam: Agência Europeia de Medicamentos (EMA), Agência Reguladora de Alimentos e Medicamentos (FDA) dos EUA e Health Canada. Dez países também aceitam decisões para autorização de comercialização da Austrália, Japão e Suíça. Argentina, Brasil, Chile e México são autoridades de referência para oito agências reguladoras. Conclusões. O uso de decisões regulatórias de outras jurisdições tornou-se prática comum na América Latina e Caribe. Treze das 20 agências reguladoras reconhecem diretamente ou abreviam o procedimento de aprovação de novos medicamentos no caso de tal aprovação já haver sido concedida por uma autoridade reguladora de outra jurisdição. A EMA, a FDA e a Health Canada são as autoridades estrangeiras nas quais as agências reguladoras da América Latina e Caribe mais confiam.

Barriers for Pharmaceutical Innovation With Focus in Cancer Drugs, the Case of Mexico.

Drug innovation does not only generate economic growth but also portrays a country's efforts toward innovation. The article reviews the current status on the innovation of the Mexican pharmaceutical industry with a focus on cancer drugs. The authors examined the scientific and nonscientific literature in search of the origin of innovative cancer drugs, as well as the regulatory frames by which these drugs are approved in Mexico. The article presents a narrative analysis of the author's experiences on the barriers that impede pharmaceutical innovation in Mexico. To the best of the authors' knowledge, there was only 1 domestic approval by COFEPRIS, the Mexican health regulatory agency, of an anticancer product developed under a repositioning approach. Among the barriers impeding drug innovation in Mexico are, but not be limited to, insufficient funds for the discovery phase; unaffordable or limited capacity for performing preclinical studies under good laboratory practices (GLP); lengthy clinical trial approval; unfavorable conditions for clinical trials for both academic and domestic pharmaceutical industry-sponsored studies; unclear policies for drug approvals and marketing. The authors state specific proposals for overcoming these barriers to generate a climate for increasing participation of academic and existing domestic pharmaceutical industry as well as to increase venture capital and favor start-up and early-stage companies. In conclusion, Mexico has the human resources and material infrastructure to innovate. The implementation of these and any other constructive proposals are just a matter of political will.

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer.

OBJECTIVE: This paper aims to describe the clinical and regulatory aspects of new drugs and indications that were approved for lung, breast, prostate, and colorectal cancer, from 2016 to 2018, in order to provide health technology assessment trends in oncology. METHODS: Data were collected from the US Food and Drug Administration (FDA) online database for new medications and indications approved for the above-mentioned types of cancer. Data regarding clinical study characteristics and regulatory information were collected. RESULTS: From 2016 to 2018, 53 percent of the FDA approvals of new drugs and indications for the most incident cancers were for oral protein kinase inhibitor monotherapy for advanced lung cancer. Since 2018, four drugs were approved as tumor-agnostic therapies. A biomarker was included in 72 percent of indications, and 58 percent of approvals were for targeted therapies, potentially heralding an end to research into conventional cytotoxic agents. A special designation for faster approval was granted in 78 percent of new approvals. The majority of the studies were open label randomized controlled trials (RCTs) (44 percent), followed by blind RCTs, single-arm clinical trials, and cohort studies. Only 14 percent of studies used overall survival as the primary end point; the vast majority used surrogate end points, and did not use patient-important outcomes. Three biosimilars were approved in the period. CONCLUSION: Advanced lung cancer therapy, mainly targeted drugs, accounted for 53 percent of approvals. Special designations for faster approval were used in 78 percent of FDA approvals, and four drugs were approved for tumor-agnostic treatment-a new form of approval.

Therapeutic value and price of the new pharmaceuticals commercialized in Argentina: Are they worth what they cost? / Valor terapéutico y precio de los nuevos fármacos comercializados en Argentina: ¿valen lo que cuestan?

In Argentina, new drugs can be authorized by presenting the drug's certificate of approval in at least one of 15 countries considered to have rigorous health surveillance, without needing to carry out a local evaluation of the efficacy, safety or added therapeutic value of the new product. In this article, we evaluate the new drugs commercialized in Argentina in 2016 using different approaches: their approval by other regulatory agencies, the demonstration of their efficacy in randomized clinical trials, types of outcomes studied, rating of their added therapeutic value using two widely recognized scales, and their sale price to the public. It is concluded that, as a reflection of what occurs in developed countries, new drugs enter the market at exorbitant prices, but the majority do not represent a significant therapeutic advancements. The result is increased risks to patients and an overburdening of the public and private funding systems.

En Argentina, los nuevos medicamentos pueden ser autorizados presentando el certificado de aprobación en al menos uno de los 15 países considerados de alta vigilancia sanitaria, sin necesidad de realizar una evaluación propia de eficacia, seguridad o valor terapéutico agregado por el nuevo producto. En este artículo, evaluamos los nuevos medicamentos comercializados en Argentina en el año 2016, utilizando diferentes enfoques: su aprobación por otras agencias reguladoras, demostración de eficacia en ensayos clínicos aleatorizados, tipo de desenlaces estudiados, calificación del valor terapéutico agregado por medio de dos escalas reconocidas y el precio de venta al público. Se concluye que, como reflejo de lo que ocurre en los países desarrollados, los nuevos medicamentos ingresan con precios exorbitantes, pero la mayoría no representa un avance terapéutico significativo. El resultado es un aumento de riesgos para los pacientes y una sobrecarga para los sistemas de financiación públicos y privados.

Valor terapéutico y precio de los nuevos fármacos comercializados en Argentina: ¿valen lo que cuestan? / Therapeutic value and price of the new pharmaceuticals commercialized in Argentina: Are they worth what they cost?

RESUMEN En Argentina, los nuevos medicamentos pueden ser autorizados presentando el certificado de aprobación en al menos uno de los 15 países considerados de alta vigilancia sanitaria, sin necesidad de realizar una evaluación propia de eficacia, seguridad o valor terapéutico agregado por el nuevo producto. En este artículo, evaluamos los nuevos medicamentos comercializados en Argentina en el año 2016, utilizando diferentes enfoques: su aprobación por otras agencias reguladoras, demostración de eficacia en ensayos clínicos aleatorizados, tipo de desenlaces estudiados, calificación del valor terapéutico agregado por medio de dos escalas reconocidas y el precio de venta al público. Se concluye que, como reflejo de lo que ocurre en los países desarrollados, los nuevos medicamentos ingresan con precios exorbitantes, pero la mayoría no representa un avance terapéutico significativo. El resultado es un aumento de riesgos para los pacientes y una sobrecarga para los sistemas de financiación públicos y privados.

ABSTRACT In Argentina, new drugs can be authorized by presenting the drug's certificate of approval in at least one of 15 countries considered to have rigorous health surveillance, without needing to carry out a local evaluation of the efficacy, safety or added therapeutic value of the new product. In this article, we evaluate the new drugs commercialized in Argentina in 2016 using different approaches: their approval by other regulatory agencies, the demonstration of their efficacy in randomized clinical trials, types of outcomes studied, rating of their added therapeutic value using two widely recognized scales, and their sale price to the public. It is concluded that, as a reflection of what occurs in developed countries, new drugs enter the market at exorbitant prices, but the majority do not represent a significant therapeutic advancements. The result is increased risks to patients and an overburdening of the public and private funding systems.

Investigación de la eficacia y criterios de aprobación de los tratamientos con medicamentos para pacientes con cáncer: una revisión / Research of effectiveness and approval criteria for treatments with medications for patients with cancer: a review

RESUMEN Los diversos trastornos malignos de los tejidos humanos afectan a una gran proporción de personas de Colombia y el mundo, lo que ha llevado al incremento de los tratamientos farmacológicos para estas enfermedades, sin que se tenga claro el real beneficio para los pacientes que los reciben. Además, se tienen dudas sobre la calidad de la evidencia en la que se basan las instituciones que avalan los tratamientos anti-cáncer con medicamentos, como son la Food and Drug Administration (FDA) y la European Medicines Agency (EMA). Este trabajo tuvo como objetivo conocer cómo se realizan los estudios de eficacia y la forma en que se aprueban los tratamientos con medicamentos que se ofrecen a las personas con cáncer; se realizó una revisión narrativa, que se basó en la formulación de preguntas que guiaron el desarrollo de los temas que se incluyeron en ella. Se hizo la búsqueda de la información en Pubmed de una forma estructurada, no sistemática. Se incluyeron artículos publicados en inglés y español, sin restricción por fecha de publicación.

SUMMARY Several malignant disorders of human tissues affect a large proportion of people in Colombia and worldwide, which has led to an increase in pharmacological treatments for these diseases, without the real benefit being clear to the patients who receive them. Furthermore, there are doubts about the quality of the evidence on which the institutions that support anticancer treatments with medications are based, such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Our objective was to know how efficacy studies are carried out and how treatments with medications offered to people with cancer are approved. A narrative review was carried out, which was based on the formulation of questions that guided the development of the topics that were included. The search strategy was done in PubMed in a structured but non-systematic way. Articles published in english and spanish were included, without restriction by publication date.

O mercado brasileiro de anticorpos monoclonais utilizados para o tratamento de câncer / The Brazilian market for monoclonal antibodies used in cancer treatment / El mercado brasileño de anticuerpos monoclonales utilizados para el tratamiento de cáncer

Resumo: Os anticorpos monoclonais (mABs) têm sido indicados como tecnologia inovadora para o tratamento de alguns tipos de câncer, por serem capazes de alvejar e matar seletivamente células tumorais. Contudo, os altos custos dessas terapias colocam em questão a sustentabilidade do acesso. Este trabalho teve como objetivo identificar as principais características dos anticorpos monoclonais, destinados ao tratamento de câncer, com registro sanitário ativo, no Brasil, em 2016. Tratou-se de uma análise descritiva retrospectiva a partir de consulta à página de Internet da Agência Nacional de Vigilância Sanitária (Anvisa), em que esses mABs foram caracterizados de acordo com antígeno-alvo, tipo de anticorpo, ano de registro, indicações terapêuticas e empresa detentora do registro. Foram identificados 14 anticorpos com ação em sete antígenos-alvo diferentes. No que diz respeito às indicações clínicas, houve uma maior frequência de linfomas, leucemias, câncer de mama e câncer colorretal. Quanto ao tipo, foram identificados três anticorpos quiméricos, seis humanizados e cinco humanos. A Roche apareceu como a empresa detentora do registro de 6 dos 14 mABs, o que representa 43% dos registros sanitários. Foi possível, a partir desses dados, discutir a ideia de medicamentos me-too no mercado de biológicos, assim como pensar as tensões existentes nesse mercado e a ideia de oligopólio diferenciado. Apesar do desenvolvimento de novos produtos, ainda que para atuar em um mesmo alvo, representar a possibilidade de um incremento competitivo e, com isso, de uma diminuição dos preços praticados pelas empresas torna-se um problema quando é a mesma empresa que lança no mercado novos anticorpos direcionados ao mesmo alvo, sem mudanças relevantes.

Abstract: Monoclonal antibodies (mABs) have been indicated as an innovative technology for the treatment of some types of cancer, since they are capable of targeting and selectively killing tumor cells. However, the high costs of these therapies raise questions as to the sustainability of access. This study aimed to identify the principal characteristics of monoclonal antibodies used in cancer treatment with active marketing authorization in Brazil as of 2016. This was a descriptive retrospective analysis based on consultation of the Brazilian Health Regulatory Agency (Anvisa) website, in which these mABs were characterized according to the target antigen, type of antibody, year of registration, therapeutic indications, and applicant. A total of 14 antibodies were identified with action on seven different target antigens. The most frequent clinical indications were for lymphomas, leukemias, breast cancer, and colorectal cancer. As for type, the study identified three chimeric, six humanized, and five human antibodies. Roche was the applicant in 6 of the 14 mABs, or 43% of the marketing authorization. It was possible to discuss the idea of me-too medicines in the biological market and the idea of a differentiated oligopoly, as well as to think about the tensions in this kind of market. It is expected that the development of new products, although to act on the same biological target, represent the possibility of a competitive increase and, as a result, a decrease in prices practiced by companies. However, this becomes a problem when it is the same pharmaceutical industry that launches on the market new antibodies directed to the same target, with no relevant changes.

Resumen: Los anticuerpos monoclonales (mABs) han sido señalados como una tecnología innovadora para el tratamiento de algunos tipos de cáncer, por ser capaces de apuntar y matar selectivamente células tumorales. No obstante, los altos costes de estas terapias ponen en cuestión la sostenibilidad del acceso. El objetivo de este trabajo fue identificar las principales características de los anticuerpos monoclonales, destinados al tratamiento de cáncer, con registro sanitario activo, en Brasil, en 2016. Se trató de un análisis descriptivo retrospectivo, a partir de la consulta a la página web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa), donde esos mABs se caracterizaron conforme el antígeno objetivo, tipo de anticuerpo, año de registro, indicaciones terapéuticas y empresa detentora de su registro. Se identificaron 14 anticuerpos con acción en siete antígenos-objetivo diferentes. En lo referente a las indicaciones clínicas, hubo una mayor frecuencia de linfomas, leucemias, cáncer de mama y cáncer colorrectal. En cuanto al tipo, se identificaron tres anticuerpos quiméricos, seis humanizados y cinco humanos. Roche apareció como la empresa detentora del registro de 6 de los 14 mABS, lo que representa un 43% de los registros sanitarios. Fue posible, a partir de esos datos, discutir la idea de medicamentos me-too en el mercado de biológicos, así como reflexionar sobre las tensiones existentes en ese mercado y la idea de oligopolio diferenciado. El desarrollo de nuevos productos, aunque sean para actuar en un mismo objetivo, representa la posibilidad de un incremento competitivo y, con ello, de una disminución de los precios practicados por las empresas. Esto se convierte en un problema cuando es la misma empresa que lanza en el mercado nuevos anticuerpos, dirigidos al mismo objetivo, sin cambios relevantes.

Suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups / Adequação às faixas etárias pediátricas de medicamentos novos registrados no Brasil de 2003 a 2013

ABSTRACT Objective To analyze suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups. Methods A descriptive study of drugs with pediatric indication included in a retrospective cohort of new drugs registered in Brazil. The evaluation of drug suitability for the pediatric age group was performed using the following criteria: suitability of dosage form and capacity to deliver the recommended dose. The drugs were considered adequate for the pediatric age groups when they met both criteria. The statistical analysis included calculation of frequencies and proportions. Results Suitability due to the drug capacity to deliver the recommended dose was greater than 80% across all age groups. Regarding suitability of the dosage form, we identified that the older the age group, the greater suitability for pediatric use. Concerning the drugs presented in solid dosage form, we showed that half were classified as inadequate for one or more pediatric age groups to whom they were indicated. The adequacy of drugs to the pediatric age group was 64.3% for preschool children, 66.7% for full-term newborns, 66.7% for premature newborns, and over 70% for other age groups. Conclusion Drugs for children aged under 6 years were less often adequate, considering the dosage form and capacity to provide the recommended dose. The availability and proportional suitability of medicines for pediatric use are greater for older age groups, according to age groups the drug is registered for.

RESUMO Objetivo Analisar a adequação às faixas etárias pediátricas dos medicamentos novos registrados no Brasil no período de 2003 a 2013. Métodos Estudo descritivo dos medicamentos com indicação pediátrica incluídos em uma coorte retrospectiva de medicamentos novos registrados no Brasil. A avaliação da adequação do medicamento à faixa etária pediátrica foi realizada empregando os seguintes critérios: adequação da forma farmacêutica e capacidade de fornecer a dose recomendada. Os medicamentos foram considerados adequados às faixas etárias pediátricas quando preencheram os dois critérios. A análise estatística compreendeu cálculo de frequências e proporções. Resultados A adequação devido à capacidade do medicamento fornecer a dose recomendada foi superior a 80% em todas as faixas etárias. Em relação à adequação da forma farmacêutica, identificou-se que quanto maior a faixa etária, maior a proporção de adequação para uso pediátrico. Em relação aos medicamentos que se apresentavam em formas farmacêuticas sólidas, evidenciou-se que metade foi classificada como inadequada para uma ou mais faixas etárias pediátricas para as quais estavam indicados. A adequação dos medicamentos à faixa etária pediátrica foi 64,3% para pré-escolares, 66,7% para recém-nascidos a termo, 66,7% para recém-nascidos prematuros e superior a 70% para as demais faixas etárias. Conclusão Os medicamentos destinados às crianças menores de 6 anos apresentaram menor frequência de adequação, considerando a forma farmacêutica e a capacidade de fornecer a dose recomendada. A disponibilidade e a proporção de adequação dos medicamentos para uso pediátrico aumentam com a elevação da faixa etária para a qual o medicamento é registrado.

Federal procurement of unlicensed medicines in Brazil; findings and implications.

BACKGROUND: There are safety concerns with using unlicensed medicines across countries including Brazil. Consequently this needs to be evaluated and concerns address if pertinent. AIM: Investigate such purchases by the Brazilian Federal Government from 2004 to 2013. METHODS: Procurement data from a public-access databank that contains procurement information of the Brazilian Federal Government. Each procured item was cross-referenced to its active drug approval status in the Brazilian National Register (DOU). Exploratory analysis and trend measures were performed for the variables for mapping and characterizing the purchases of non-market approved drugs. RESULTS: 614 (0.14%) purchases in ten years corresponding to 64 unlicensed medicines - some of which had orphan drug status - and 48 different active substances; with a growing trend in recent years. Medicines in 51% of purchases were procured before obtaining marketing approval - with eventual refusals occurring in 17.8% and cancellation due to lack of efficacy and/or safety concerns in 1.1%. Health litigation accounted for 81.9% of purchases and growing in recent years. CONCLUSIONS: Overall a low rate of unlicensed medicine use. However there are concerns given the current regulations in Brazil and the recent increase in the use of unlicensed medicines with increased litigation.

Postmarketing Safety Events Relating to New Drugs Approved in Brazil Between 2003 and 2013: A Retrospective Cohort Study.

This study investigated postmarketing safety events (PMSEs) for new drugs approved in Brazil and evaluated whether a range of drug characteristics influenced the time between approval and the first PMSE. This retrospective study included new drugs registered between 2003 and 2013 by the National Health Surveillance Agency (ANVISA), which is responsible for medicines approval in Brazil. PMSEs were defined as any drug safety alert or drug withdrawal from the market. The existence of risk evaluation and mitigation strategies (REMS) by the US Food and Drug Administration (FDA) and Brazil were recorded. A Kaplan-Meier survival curve of the period between the date of ANVISA registration and the PMSE was calculated. We found a statistically significant difference between the time to PMSE for drugs with an FDA REMS compared with those without a REMS, with a log rank value (Mantel Cox) of 0.002. There was no association between the time to PMSE and the other drug characteristics investigated. This study demonstrated that the frequency of PMSEs for new drugs approved by ANVISA was statistically associated with the existence of an FDA REMS. The time between approval and first PMSE was shorter for drugs with an FDA REMS, and this finding may contribute to improved awareness of the risk/benefit balance required to ensure continued safe and effective use of new drugs.

Pharmaceutical lobbying in Brazil: a missing topic in the public health research agenda

ABSTRACT In the US, where registration of lobbyists is mandatory, the pharmaceutical industry and private health-care providers spend huge amounts of money seeking to influence health policies and government decisions. In Brazil, where lobbying lacks transparency, there is virtually no data on drug industry expenditure to persuade legislators and government officials of their viewpoints and to influence decision-making according to commercial interests. Since 1990, however, the Associação da Indústria Farmacêutica de Pesquisa (Interfarma - Pharmaceutical Research Industry Association), Brazilian counterpart of the Pharmaceutical Research and Manufacturers of America (PhRMA), main lobbying organization of the US pharmaceutical industry, has played a major role in the advocacy of interests of major drug companies. The main goals of Interfarma lobbying activities are: shortening the average time taken by the Brazilian regulatory agency (ANVISA) to approve marketing authorization for a new drug; making the criteria for incorporation of new drugs into SUS (Brazilian Unified Health System) more flexible and speeding up technology incorporation; changing the Country's ethical clearance system and the ethical requirements for clinical trials to meet the need of the innovative drug industry, and establishing a National Policy for Rare Diseases that allows a prompt incorporation of orphan drugs into SUS. Although lobbying affects community health and well-being, this topic is not in the public health research agenda. The impacts of pharmaceutical lobbying on health policies and health-care costs are of great importance for SUS and deserve to be investigated.

Registro y entrega de licencias de medicamentos - Áreas y conceptos claves: síntesis rápida de evidencia de alcance / Registration and delivery of drug licenses - Areas and key concepts: rapid synthesis of scoping evidence

ANTECEDENTES Y OBJETIVO Una Agencia Reguladora Nacional de Medicamentos es una entidad que se encarga de la regulación de 4 funciones básicas: Registro de productos, Entrega de licencias, Inspección y Vigilancia, y Control de precios. Sin embargo, no todos los países cuentan con una organización que reúna las 4 funciones aquí detalladas. En esa línea, Chile ha creado un grupo técnico para la creación y acreditación de esta agencia, de manera de contar con algunas ventajas en términos de barreras arancelarias. Esta agencia velaría por la alta calidad de los medicamentos utilizados en el país. En este contexto el Coordinador del Grupo Técnico Asesor para el Directorio del Sistema Nacional de Regulación, control y vigilancia de medicamentos solicita esta síntesis de evidencia con el objetivo de informar a la toma de decisiones respecto del impacto de contar con una Agencia Nacional de Regulación de Medicamentos. METODOLOGÍA Utilizando palabras clave como "Registro", "Medicamentos", "Política farmacéutica", "Regulación", "Autoridades reguladoras" y "Licencias" se buscó en las bases de datos Cochrane Library, PDQ y Health System Evidence No se restringió el tipo de estudio buscado ni los años de realización. Se realizaron búsquedas por Título y Abstract. RESULTADOS El resumen utiliza 13 estudios Los problemas identificados en la literatura que podrían estar relacionados a registro y entrega de licencias son: Medicamentos falsificados y adherencia a tratamientos Los ámbitos/áreas de interés encontrados en la literatura son: Medicinas esenciales, uso de genéricos y sistemas de información Por último, intervenciones comúnmente mencionadas en la literatura, y que podrían estar asociadas a registro y entrega de licencias para medicamentos son: Lista de fármacos preferidos, monitoreo de fármacos de interés particular y proceso de autorización de fármacos.

Condición de venta de analgésicos antiinflamatorios no esteroides, legalmente autorizados para su comercialización en Colombia. Estrategias de uso racional / Condition of sale of non-steroidal anti-inflammatory drugs authorized for marketing in Colombia. Strategy of rational use

La condición de comercialización (venta libre, con fórmula médica, bajo control especial o para uso hospitalario exclusivamente) determina las circunstancias en las cuales puede ser publicitado y comercializado un medicamento. La venta libre no involucra una consulta al equipo de salud, quienes no participan de la selección del medicamento, su dispensación ni seguimiento fármaco-terapéutico. El presente trabajo, mediante un estudio observacional descriptivo de corte transversal desarrollado partiendo del universo de registros sanitarios de medicamentos en Colombia, identifica y describe las variaciones en la condición de venta de analgésicos antiinflamatorios no esteroides. Para este grupo farmacológico, de gran consumo en el país, predominan la modalidad de registro "fabricar y vender", las formas farmacéuticas sólidas no estériles, la condición de venta con fórmula médica y la vía de administración enteral; asimismo, predomina como principio activo el diclofenaco, seguido de ibuprofeno y piroxicam. Ocho de los principios activos de este grupo farmacológico poseen doble condición de venta (venta sin prescripción facultativa o libre y venta con fórmula médica) y alcanzan el 70% de las autorizaciones de comercialización de aines en Colombia. Se evidencia una relación entre la cantidad principio activo por unidad posológica y la condición de venta autorizada, relación que no es evidente con respecto a la indicación.

The commercialization status (otc, under medical prescription, under special monitoring or for hospital use only) sets out the circumstances under which it may be publicized and marketed a drug. The otc does not involve consulting the health team, who do not participate in the selection of the drug, its dispensing or therapeutic monitoring. Present work through an observational, descriptive, cross-sectional study from the universe of Colombian drug approvals, identify and describe the variations in the condition of sale of non-steroidal anti-inflammatory drugs. For this pharmacological group, widely consumed in the country, dominated the modality "make and sell", the non-sterile solid dosage forms, the condition of sale under prescription and the enteric route of administration, likewise predominate as active substance diclofenac, followed by ibuprofen and piroxicam. Eight of the active ingredients of this pharmacological group have double condition of sale (otc and under medical prescription) achieving 70% of marketing authorization for nsaids in Colombia. It is evidenced a relationship between the amount of active substance per dosage unit and the commercialization status, a relationship that is not evident with respect to the indication.

Questões relevantes para a aprovação de medicamentos biossimilares / Relevant issues to biossimilars licensing

Medicamentos genéricos podem ser introduzidos a baixo custo no mercado quando a patente do medicamento inovador expira. Os resultados dos testes que demonstram a segurança e eficácia do produto inovador podem ser extrapolados para o genérico, simplificando sua aprovação. Este paradigma não pode ser aplicado aos biofármacos, grandes moléculas de difícil caracterização, onde pequenas alterações no processo de manufatura influenciam as propriedades biológicas e clínicas do produto e podem resultar em diferenças nos seus perfis de eficácia e segurança. Não sendo possível demonstrar a identidade entre biofármacos, eles não podem ser aprovados como simples genéricos e necessitam regulamentação específica. Neste trabalho foram feitos um levantamento bibliográfico das principais questões envolvidas na aprovação de versões similares de biofármacos e uma análise comparativa da situação regulatória nos principais mercados - EUA e União Europeia - a partir de legislação, projetos de lei, diretrizes e referências técnicas de suas agências regulatórias - FDA (Food and Drug Administration) e EMEA (European Medicines Agency), respectivamente, visando à discussão do caso brasileiro. A partir da legislação e diretrizes estudadas conclui-se que, apesar de Brasil, Europa e Estados Unidos estarem em estágios distintos de definição de sua estrutura regulatória para biossimilares, é possível identificar algumas semelhanças nas abordagens seguidas, como a necessidade de tratamento diferenciado para cada classe de produto (ou um enfoque caso a caso) e de um exercício de comparabilidade passo a passo, cujos resultados definirão a quantidade de dados e estudos clínicos e não clínicos necessários. Entretanto, questões como intercambialidade e substituição automática dos produtos de referência por biossimilares ainda não estão claramente definidas. Do ponto de vista sanitário, a Europa apresenta uma postura mais conservadora, enquanto que EUA e Brasil parecem estar construindo um arcabouço mais flexível. Ao lado das questões sanitárias, entretanto, destacam-se as questões econômicas, de grande importância na legislação dos EUA e Europa e não abordadas na regulamentação brasileira - o que pode trazer insegurança aos produtores interessados neste mercado.

When the patent of a drug expires, low cost generics may be introduced in market. Trial results that demonstrate the safety and efficacy of the reference product can be extrapolated to the generic, simplifying the approval process. This paradigm cannot be applied to biopharmaceutical products, large molecules difficult to be characterized. Minor changes in the production process can influence the biological and clinical properties of the product and result in differences in efficacy and safety profiles. It is not possible to demonstrate the identical nature of biopharmaceuticals arising from different manufacturing sources, so they cannot be approved as simple generics and need specific regulation. A bibliographical survey of the main issues involved in the approval of similar versions of biopharmaceuticals was performed as well as a comparative analysis of the regulatory situation in the largests pharmaceutical markets - U.S. and European Union - based on legislation, draft laws, guidelines and technical references issued by their regulatory agencies - FDA (Food and Drug Administration) and EMEA (European Medicines Agency), respectively, in order enlight the discussion now taking place in Brazil. Based on the laws and guidelines studied, it is concluded that, although Brazil, Europe and the United States are at different stages of setting their regulatory framework for biossimilars, it is possible to identify some similarities in approach, such as the need for different treatment for each product class (or a case by case focus) and a step by step comparison exercise, the results of which will define the amount of data and non-clinical and clinical studies required. However, issues such as interchangeability and automatic substitution of biossimilars for reference products are not yet clearly defined. From the sanitary point of view, Europe has a more conservative posture, while the U.S. and Brazil seem to be building a more flexible framework. Besides the health issues, however, we highlight the economic issues, of great importance in Europe and U.S. legislation, and not addressed in the Brazilian regulation - which can bring insecurity to producers interested in this market.

Revisión documental de los productos naturales legalmente autorizados para su mercadeo en Colombia / Documental revision of the natural products authorized for marketing in Colombia

Introducción: El grupo de los productos naturales ha cobrado gran interés en los últimos años debido a la creencia popular que son eficaces y más seguros que los medicamentos de síntesis o por recientes tendencias en salud que buscan suplementar la alimentación.Objetivo: Describir el grupo de los productos naturales desde el punto de vista de la autoridad sanitaria.Metodología: Estudio observacional descriptivo de corte transversal a partir del universo de los Registros Sanitarios de Productos Naturales que presenta la base de datos del Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Autoridad Sanitaria Colombiana).Resultados: Aproximadamente la mitad de los productos naturales legalmente aceptados para su mercadeo son productos fitoterapéuticos y la otra mitad la componen los suplementos dietarios junto con los productos de uso específico. La especie vegetal con mayor número de autorizaciones de comercialización es la alcachofa (Cynara scolymus), seguida de caléndula (Calendula officinalis), valeriana (Valeriana officinalis), ajo (Allium sativum) y ginkgo (Ginkgo biloba). Hay un predominio del empleo de especies foráneas en los productos fitoterapéuticos comercializados. Se propone una clasificación novedosa del órgano de la planta o droga empleado en la producción con la cual es evidente el mayor uso de las hojas respecto a cualquier otro órgano. Cápsulas, tabletas y soluciones son las formas farmacéuticas predominantes...

Introduction: The group of natural products has gained much interest in recent years because of the popular belief that they are effective and more secure than synthetic medications, or because of recent health tendencies seeking to supplement nutrition. Objective: To describe the group of natural products from a sanitary authority point of view. Methodology: Observational, descriptive, cross-sectional study from the universe of Drug approvals of Natural Products presented by a database from the Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Colombian Sanitary Authority). Results: Nearly half of the natural products legally accepted for marketing are herbal medicines and the other half are dietary supplements, along with specific-use products. The vegetable species with the greatest number of commercialization authorizations is artichoke Cynara scolymus (alcachofa), followed by calendula (Calendula officinalis), valerian (Valeriana officinalis), garlic (Allium sativum), and ginkgo (Ginkgo biloba). Foreign species predominate in the fabrication of commercialized herbal medicines. A novel classification is proposed of the plant organ or drug employed in the production with which it is evident that leaves are used more with respect to any other plant organ. Capsules, tablets, and solutions are the predominant pharmaceutical forms...