HTA criteria adopted in different models of public healthcare systems for orphan drugs: A scoping review.

Access to drugs for rare diseases constitutes a challenge to healthcare systems, especially those with public funding. This study aimed to map and summarize the criteria used by HTA agencies in different healthcare systems to evaluate reimbursement recommendations for orphan drugs. A comprehensive literature search was performed on the databases PubMed, LILACS, Scopus, and Embase and the gray literature (Google Scholar and websites of HTA agencies). Publications addressing the criteria used by HTA agencies in countries with public healthcare systems when evaluating reimbursement recommendations for orphan drugs were included. This scoping review included 23 studies published between 2014 and 2023, mostly consisting of reviews of HTA reports, guidance documents, and original articles. The criteria were mapped from 19 countries and ranked within three models of healthcare systems (National Health System, National Health Insurance, and Social Health Insurance). All models shared concerns about unmet needs and disease nature. In addition, NHS countries (e.g., United Kingdom, Sweden, and Italy) prioritized innovation and system-level impact, while SHI countries (e.g., Germany, France, the Netherlands) usually valued budget impact and employed expedited evaluation processes. This review provides a comprehensive understanding of the general tendencies of each healthcare system model in establishing differentiated criteria to address the challenges posed by the limited evidence and investment in the field of rare diseases.

Estratégias de Avaliação de Tecnologias em Saúde (ATS) para medicamentos para doenças raras: uma revisão rápida de escopo / Health Technology Assessment (HTA) strategies for drugs in rare diseases: a rapid scope review

A Avaliação de Tecnologias em Saúde (ATS) considera os domínios de benefícios clínicos, perfil epidemiológico, inovação, custo-efetividade, ética e de equidade no processo de decisão dos gestores em saúde. No contexto dos medicamentos para doenças raras, é desafiador o trabalho da ATS, dada a baixa disponibilidade de evidências robustas e o alto custo unitário das tecnologias. O objetivo da revisão foi analisar as estratégias disponíveis de avaliação das demandas de incorporação de medicamentos para o tratamento de doenças raras em sistemas de saúde. Foi realizada uma revisão rápida com busca estruturada na base de dados MEDLINE (via PubMed), Cochrane Library e Health Systems Evidence. Incluíram-se estudos sobre estratégias de avaliação de medicamentos utilizados para tratamento de doenças raras. Adicionalmente, foram realizadas buscas nas Agências de ATS do Brasil, Austrália, Nova Zelândia, Canadá, Reino Unido, França, Estados Unidos e Alemanha. A síntese dos resultados foi qualitativa com o agrupamento dos achados nos seguintes eixos temáticos: Segurança e efetividade, Custo-efetividade, Impacto orçamentário e Perspectiva da sociedade. Foram identificadas 267 publicações, sendo selecionadas 16 das bases de dados indexadas e 7 da literatura cinzenta. Com a análise dos documentos, pode-se concluir que a adoção de critérios específicos harmonizada com o atual modelo de ATS é um possível caminho a ser seguido no contexto dos medicamentos para doenças raras. Concomitante a isso, abordagens no sentido de incentivo a pesquisa e produção de dados de mundo real e a criação de comitês específicos para tratativa do tema nas agências de ATS apresentam-se como alternativa para lidar com as fragilidades no contexto de doenças raras.

The Health Technology Assessment (HTA) considers evidence regarding clinical benefits, epidemiological profile, innovation, cost-effectiveness, ethics and equity in its assessment process to support managers' decisions. In the context of drugs in rare diseases, the work of the ATS is challenging given the low availability of evidence and the high cost of technologies. The objective of the review was to analyze the available strategies for evaluating the demands for incorporating drugs for the treatment of rare diseases in health systems. A rapid review was performed with a structured search in the MEDLINE database (via PubMed), the Cochrane Library and Health Systems Evidence. Studies on strategies for evaluating drugs used to treat rare diseases were included and, additionally, searches were carried out in ATS Agencies in Brazil, Australia, New Zealand, Canada, United Kingdom, France, United States and Germany. The synthesis of the results was qualitative, grouping the major ones into thematic axes: Safety and effectiveness, Cost-effectiveness, Budgetary impact and Society's perspective. 267 publications were identified, 16 selected from indexed databases and 7 from gray literature. With the analysis of the documents, it can be concluded that the adoption of specific criteria harmonized with the current ATS model is a possible path to be followed in the context of drugs for rare diseases. At the same time, approaches to encourage research and the creation of specific committees to deal with the issue in HTA agencies would complement actions towards the consolidation of this work.

Advancing rare disease policy in Latin America: a call to action.

People living with a rare disease are amongst the most vulnerable groups in society. They have been historically marginalised and systematically stigmatised. It is estimated that 300 million people worldwide live with a rare disease. Despite that, many countries today, especially in Latin America, still lack consideration of rare diseases in public policies and national laws. Based on interviews with patient advocacy groups in Latin America, we aim to provide recommendations for lawmakers and policymakers in Brazil, Peru, and Colombia on how to improve public policies and national legislation for persons living with rare diseases in these three countries.

Enfermedades raras en la infancia. Visión gastroenterológica / Rare Diseases in Childhood. Gastroenterological View

Introducción: Las enfermedades raras conforman las afecciones de baja prevalencia que asociadas a los medicamentos huérfanos representan un problema sanitario y social mundial. Objetivo: Revisar los aspectos más sobresalientes relacionados con las enfermedades raras, con una visión gastroenterológica, y su repercusión en la infancia. Métodos: Se realizaron búsquedas no estructuradas de publicaciones en español e inglés en PubMed, Google Scholar, Scimago, SciELO, desde enero 2010 hasta agosto 2021. Se usaron los términos: enfermedades raras, conceptualización, prevalencia, epidemiología, medicamentos huérfanos y ética. Análisis y síntesis de la información: Se revisaron las enfermedades raras en la infancia, criterios conceptuales, epidemiología global, enfermedades más reconocidas con énfasis en gastroenterología. Se destacó la prevalencia, vínculo genético, importancia social, dilema diagnóstico y categorías; repercusión de los tratamientos con medicamentos huérfanos, sus costos y problemas éticos. Se resaltó la incidencia de enfermedades digestivas y el valor de la endoscopia y la biopsia en el diagnóstico. Conclusiones: Se documentaron las enfermedades raras en la infancia, y se analizaron como problema mundial, sanitario y social. El desarrollo de la técnica y de la ciencia, resultaron contribuciones decisivas que variaron criterios sobre diferentes afecciones catalogadas como raras(AU)

Introduction: Rare diseases are the conditions of low prevalence associated with orphan drugs and they represent a global health and social problem. Objective: To review the most outstanding aspects related to rare diseases, with a gastroenterological view, and their impact on childhood. Methods: Unstructured searches for publications in Spanish and English in PubMed, Google Scholar, Scimago, SciELO were conducted, from January 2010 to August 2021. The terms rare diseases, conceptualization, prevalence, epidemiology, orphan drugs and ethics were used. Analysis and synthesis of information: Rare diseases in childhood, conceptual criteria, global epidemiology, and the most well-known diseases with emphasis on gastroenterology were reviewed. Prevalence, genetic link, social importance, diagnostic dilemma and categories, also the impact of orphan drug treatments, their costs and ethical problems were highlighted. The incidence of digestive diseases and the value of endoscopy and biopsy in diagnosis were highlighted. Conclusions: Rare diseases in childhood were documented and analyzed as a global health and social problem. The development of technique and science were decisive contributions that varied criteria on different conditions classified as rare(AU)

Knowledge level of medical students and physicians about rare diseases in Lima, Peru.

Rare diseases (RDs) affect up to 8% of the world's population, and unfortunately, health professionals have a low level of knowledge regarding the impacts of RDs on the social, psychological, and economic spheres of the patients and their families; hence, RD management is inadequate, consistently empirical, and precarious. The objective of this study was to determine the knowledge level of the medical students from a non-state university and physicians from Lima, Peru of RDs through a virtual survey for an analytical cross-sectional study. A total of 338 medical students and 382 physicians were surveyed. Results showed that several of the respondents (68.1% of students and 48.7% of physicians) had heard of the term "rare disease", but only a few stated that they had received any kind of training specific to it. Of the physicians, 46.6% considered that there should be a course about RDs in medical curricula, and more than 60% considered RDs a public health problem. Most respondents prioritized the planning of a higher budget for common diseases and believe it is convenient to allocate a specific fund for RDs. More than half of the participants had a very poor knowledge level. Due to students and physicians' low level of general knowledge of RDs, it is important to raise awareness and improve their education about these pathologies because this will have beneficial effects for RD patient care.

Doenças raras no Congresso Nacional brasileiro: análise da atuação parlamentar / Rare diseases in the Brazilian National Congress: analysis of parliamentary action / Enfermedades raras en el Congreso Nacional brasileño: análisis de la actuación parlamentaria

Políticas públicas que atendam a população de doenças raras no Brasil são cada vez mais discutidas, seja para acesso aos medicamentos, para atenção multidisciplinar, alternativas terapêuticas ou representatividade. Apesar de o Ministério da Saúde ter publicado em 2014 a Portaria nº 199, que instituiu a Política Nacional de Atenção Integral às Pessoas com Doenças Raras, aprovando as Diretrizes para Atenção Integral às Pessoas com Doenças Raras no âmbito do Sistema Único de Saúde (SUS), essa população segue desamparada frente às peculiaridades de seus tratamentos. Neste cenário, associações de pacientes passaram a buscar espaços de representação política, provocando cada vez mais iniciativas legislativas no Congresso Nacional com vistas a alternativas para os milhões de brasileiros que vivem ou convivem com doenças raras. Por meio de uma pesquisa documental qualitativa, o artigo considera todos os projetos apresentados até agosto de 2020 com foco neste tema, identificando os principais parlamentares que atuam nele, as características biográficas comuns entre eles, em qual etapa do ciclo de políticas públicas o tema está no Congresso Nacional e, com isso, pretende identificar um possível caminho para a consolidação de uma política. Observou-se que a atuação em doenças raras independe de alinhamento político partidário, sendo uma pauta compartilhada por grupos antagônicos, mas que enfrenta o desafio de apenas 18 parlamentares terem sidos os responsáveis por 50% de todas as matérias legislativas já apresentadas sobre isso. Além disso, observou-se também que os parlamentares preferem impulsionar o debate e dar visibilidade ao tema do que investir em novas tentativas de mudanças legais e regulatória.

Public policies that serve the Brazilian population with rare diseases are increasingly discussed, either regarding access to medicines, multidisciplinary care, therapeutic alternatives, or representativeness. Although the Brazilian Ministry of Health published in 2014 the Ordinance n. 199, which instituted the Brazilian National Policy of Integral Care for People with Rare Diseases and approving the Guidelines for Integral Care to People with Rare Diseases under the Brazilian Unified National Health System (SUS), this population remains unaided regarding the peculiarities of their treatments. In this scenario, patient associations began to seek spaces for political representation, increasingly provoking legislative initiatives in the Brazilian National Congress, seeking for alternatives for the millions of Brazilians living with rare diseases. By using a qualitative documentary research, the study considers all projects presented until August 2020 on this topic, identifying the main parliamentarians involved, their biographical characteristics, and at which stage of the public policy cycle this topic is in the Brazilian National Congress; thus, identifying a possible path for the consolidation of a policy. We observed that the actions regarding rare diseases are independent of any political party alignment, being an agenda shared by antagonistic groups. This agenda, however, faces the challenge of having only 18 parliamentarians responsible for 50% of all the legislative matters already presented. Furthermore, we also observed that parliamentarians prefer to boost the debate and give visibility to the subject than to invest in new attempts at legal and regulatory changes.

Las políticas públicas que asisten a la población que sufre enfermedades raras en Brasil son cada vez más discutidas, ya sea en cuanto al acceso a medicamentos, a la atención multidisciplinaria, a alternativas terapéuticas o a la representatividad. Aunque el Ministerio de Salud brasileño publicó la Ordenanza nº 199 en el 2014, que estableció la Política Nacional de Atención Integral a las Personas con Enfermedades Raras, y aprobando las Directrices para la Atención Integral a las Personas con Enfermedades Raras en el ámbito del Sistema Único de Salud (SUS), esta población permanece impotente ante las peculiaridades de sus tratamientos. En este escenario, las asociaciones de pacientes comenzaron a buscar espacios de representación política, dando lugar a cada vez más iniciativas legislativas en el Congreso Nacional brasileño con vistas a alternativas para los millones de brasileños que viven o conviven con enfermedades raras. Por medio de una investigación documental cualitativa, este artículo considera todos los proyectos presentados hasta agosto del 2020 centrados en este tema, identificando a los principales parlamentarios que actúan en él, las características biográficas comunes entre ellos, en qué etapa del ciclo de políticas públicas se encuentra el tema en el Congreso Nacional brasileño y, con ello, identificar un posible camino para la consolidación de una política. Se observó que la actuación relacionada con enfermedades raras no depende de la alineación político-partidista, ya que es una agenda compartida por grupos antagónicos, pero que se enfrenta al desafío de que solo 18 parlamentarios hayan sido los responsables del 50% de todos los asuntos legislativos que ya se presentaron al respecto. Además, también se observó que los parlamentarios prefieren impulsar el debate y dar visibilidad al tema que invertir en nuevos intentos de cambios legales y regulatorios.

Caracterización de las solicitudes de importación de medicamentos vitales no disponibles años 2016 y 2017 en Colombia / Characterization of the import applications for unavailable vital medicines in 2016 and 2017 in Colombia

Resumen En este estudio se analizaron las solicitudes de importación de Medicamentos vitales no disponibles (MVND) presentadas al INVIMA y los registros de solicitudes de recobros presentados en la ADRES por MVND, en el periodo 2016-2017. De las 2321 solicitudes de importación de MVND, el 76% fueron autorizadas. Se identificaron 88 solicitantes, 73 subgrupos terapéuticos y 195 principios activos, así como 368 diagnósticos. El 66% de los pacientes registrados en las solicitudes de importación se encuentran vinculados al régimen contributivo, en menor proporción al régimen subsidiado y al régimen especial o excepcional. En solicitudes de recobros asociados a MVND por vía judicial, se observó que, el monto solicitado por recobro fue de USD 8.577.583, equivalentes a 38483 UPCs. Los resultados mostraron que la implementación del decreto 481 de 2004 ha sido útil para garantizar el acceso a medicamentos para enfermedades raras, aunque no es ajena a la inequidad estructural de acceso a servicios de salud y medicamentos del SGSSS y que generan impacto, no solo en la salud pública, si no en el presupuesto asignado, bien sea por el alto costo que implica su importación o por la falta de regulación de estos dentro del mercado nacional.

Abstract This study analyzed the import applications for unavailable vital medicines (MVND) submitted to INVIMA and the records of MVND reimbursement requests submitted to the ADRES in the 2016-2017 period. Approximately 76% of the 2,321 MVND import applications were authorized. Eighty-eight applicants, 73 therapeutic subgroups, 195 active ingredients, and 368 diagnoses were identified. Most of the patients registered in the import applications (66%) are linked to the contributory regime, to a lesser extent to the subsidized regime and the Special or exceptional regimes. The total value of the reimbursement requests related to MVND granted by lawsuits, was USD 8,577,583, equivalent to 38,483 UPCs. The results showed that the implementation of Decree N° 481/2004 has ensured access to medicines for rare diseases. However, it is not alien to the structural inequality of access to health services and medicines of the Colombian Health System, which impacts public health and the allocated budget, either because of the high cost of importing MVND or because of the lack of MVND regulation within the national market.

Cost-Effectiveness of Nusinersen and Universal Newborn Screening for Spinal Muscular Atrophy.

OBJECTIVE: To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). STUDY DESIGN: A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. RESULTS: Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. CONCLUSION: Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.

A civil society view of rare disease public policy in six Latin American countries.

Patients with rare diseases across the world struggle to access timely diagnosis and state-of-the-art treatment and management of their conditions. Several recently published reviews highlight the importance of country efforts to address rare diseases and orphan drugs policy comprehensively. However, many of these reviews lack depth and detail at the local level, which we believe is necessary for rare disease advocates to identify and prioritize opportunities for strengthening each country's policy framework.We asked leading patient advocates from civil society organizations their views on rare disease public policy in Argentina, Brazil, Chile, Colombia, Mexico, and Peru with a focus on whether specific laws and regulations in these six Latin American countries have been promulgated. From December 2018 to March 2019 we supplemented their perspectives with evidence from accessible literature using key search terms. For each country, we prepared a detailed analysis on how laws or other policy initiatives took shape and the steps taken since to implement them. This allowed us to identify five broad policy categories for subsequent analysis: national laws, national regulations, health system incorporation of rare disease treatments, care delivery, and patient engagement.By describing the different approaches, challenges and timelines across six countries, our research demonstrates that strengthening rare disease policy first requires a common understanding and local consensus of each country's recent past and current situation. Subsequent analysis based on a set of common policy dimensions led us to where we believe salient opportunities lie for each of these countries to strengthen their overall policy framework for rare disease patients.

International experiences in multicriteria decision analysis (MCDA) for evaluating orphan drugs: a scoping review.

Introduction: Orphan diseases are low-prevalence conditions with chronically debilitating or life-threatening consequences. Their treatments are generally called orphan drugs (OD). Health-technology assessment processes have traditionally considered cost-effectiveness analysis (CEA), when making reimbursement and pricing decisions for health-care plans. Valuing OD with standard CEA raises important issues due to uncertain evidence, inability to meet cost-effectiveness thresholds for reimbursement and high budget impact, among others. Multi-criteria decision analysis (MCDA) allows to overcome these issues and improve the technical and ethical quality of decisions regarding prioritization, coverage, and reimbursement of OD. Areas covered: A scoping review was conducted in order to characterize MCDA frameworks for assessing OD and implementation experiences. We reviewed electronic databases (Medline, Embase, Cochrane Library, EBSCO, CINAHL, EconLit, Web of Science, LILACS, Google Scholar) key journals (Orphanet Journal of Rare Diseases and Value in Health) and organization repositories. Expert opinion: The theoretical framework for MCDA considers areas related to characteristics of orphan diseases and their technologies' clinical and economic impact. Participation processes are critical in incorporating societal values in weighting different dimensions and constructing decision rules. Local implementation pilots considering different stakeholders are necessary in order to pinpoint specific barriers and opportunities.

Las enfermedades raras / Rare diseases

A partir de la década de los 80, las enfermedades raras han ido adquiriendo un lugar prioritario en los programas de salud y en la opinión pública. Se definen como aquellas que tienen una prevalencia menor a 1:2.000 individuos. En general son enfermedades crónicas, invalidantes y en más de un 80% de origen genético. Se estima que existen entre 7.000 y 8.000 enfermedades raras y que afectan al 6-8% de la población. Dada la baja prevalencia específica de cada afección, hay muy poco conocimiento de parte de la comunidad médica en relación a su diagnóstico y manejo. En este artículo se discute la importancia del diagnóstico de precisión, para su adecuado manejo y asesoramiento genético, también se muestra la importancia del trabajo en redes en las enfermedades de baja prevalencia y se destaca el rol fundamental de las agrupaciones de padres y familiares en promover políticas de salud para los afectados.

From the early 80's rare diseases had achieved a priority role in national health programs and in public opinion. Rare diseases are define as the ones who have a prevalence lower than 1:2000 habs. Generally, they are chronic and life threatening diseases and more than 80% of them are from genetic origin. It is estimated that there are between 7,000 and 8,000 different rare diseases affecting 6-8% of world population. Due to the low prevalence of each disease, there are very poor knowledge in the medical community about their diagnosis and management. In this review we discuss about the importance of the precise molecular diagnosis for the best treatment and genetic counselling; we also showed the importance of working in network in these diseases of low prevalence and we discuss about the fundamental role of parents associations in promoting public health politics for affected people.

Clinical genetics and public policies: how should rare diseases be managed?

The implementation of a specific policy for rare diseases in the Brazilian Unified Health System presents challenges in terms of its rationale. Recognizing the importance of rarity in the context of public health means understanding genetics as one of the dimensions of disease and accepting that Brazil is undergoing a period of transition in health indicators. Although most rare diseases lack pharmacological treatment and genetic counseling constitutes the best strategy for their prevention, the cost of "orphan drugs" and their consequent lack of cost-effectiveness are still claimed as hurdles to the implementation of public policies in this field. Epidemiological aspects should not be used as isolated criteria for prioritization in public policies

Propuesta de normativa de registro sanitario para los "medicamentos huérfanos" en la República Bolivariana de Venezuela / Proposal for a health registration regulation for "orphan drugs" in the Bolivarian Republic of Venezuela

Los medicamentos huérfanos son aquellos requeridos para diagnosticar, prevenir o tratar enfermedades poco frecuentes, pero que pueden ser graves y debilitantes. Este trabajo tiene como objetivo proponer la implementación de una normativa de registro sanitario específica para los medicamentos huérfanos en la República Bolivariana de Venezuela, considerando la situación actual de salud y las necesidades de la población, a fin llegar a todos los niveles, facilitando la disponibilidad del mayor número de medicamentos que son requeridos por un grupo reducido de pacientes. Es necesario que las autoridades sanitarias en Venezuela fortalezcan el sistema de salud pública estableciendo políticas para satisfacer las necesidades de la población en general pero que también incluya a las minorías. Se plantean las consideraciones técnicas, legales, fiscales y regulatorias necesarias para la implementación de esta normativa, así como los criterios de inclusión para clasificar un medicamento dentro la categoría de "huérfanos". La metodología utilizada fue de tipo documental, haciendo énfasis en el análisis teórico y conceptual del material a fin de elaborar la propuesta de la normativa para medicamentos huérfanos en la República Bolivariana de Venezuela. Se realizó un análisis teórico de la información obtenida para determinar la situación actual nacional e internacional a fin de obtener los resultados que sirvieron de base para desarrollar la propuesta.

Orphan drugs are those required to diagnose, prevent or treat rare diseases but that may be severe and debilitating; besides, reduce the quality of life of patients and their families. This project aims to propose a special regulation for Orphan Drugs in the Bolivarian Republic of Venezuela taking into account the current health situation and needs of the population in order to reach all levels by facilitating the availability of a bigger amount of drugs required by a small group of patients. It is necessary for health authorities in Venezuela to strengthen the public health system by establishing policies to meet the needs of general population but also include minorities. Technical, legal and regulatory considerations arise for the implementation of this normative, as well as the inclusion criteria for drugs within the category of "orphans". The methodology used is documentary, as it emphasizes the theoretical and conceptual analysis of the material for the proposed regulation for orphan drugs in the Bolivarian Republic of Venezuela. A theoretical analysis of the information was made to determine the current national and international situation in order to obtain the results as a basis to develop the proposal.