HTAi 2023 LATAM Program FINAL

2023 2023 FORO DE POLITICAS LATIN AMERICA EN EVALUACIÓN DE POLICY FORUM TECNOLOGÍAS SANITARIAS EN LATINOAMERICA How new access schemes, including risk-sharing agreements, can ¿Cómo los nuevos esquemas de acceso, contribute to coverage decisions incluyendo los acuerdos de riesgo compartido, pueden contribuir a las Renaissance Santiago Hotel decisiones de cobertura? Santiago, Chile | August 13-15, 2023 Renaissance Santiago Hotel Santiago de Chile | 13-15 de agosto 2023

Welcome | Bienvenida Welcome from the HTAi Latin Policy Forum Chair Bienvenida del Presidente del Foro Latino de Políticas de HTAi Dear colleagues, The theme chosen for this occasion is “How new access schemes, including risk-sharing agreements, Welcome to HTAi’s VIII Latin American Health can contribute to coverage decisions”, and it has Technology Assessment Policy Forum! been selected based on the preferences and needs expressed by participants in previous years. As in previous years, our Forum continues to offer a space for neutral and independent debate on topics Finally, we take this opportunity to formally of common interest for senior professionals from thank all the speakers for their presentations and public and private institutions in connection with excellent predisposition, as well as the members of strategic decision-making on health technology the Organizing Committee of this Forum for their matters. contribution and guidance in the preparation of the basic document, as well as in the design of the The last few years have been challenging for agenda, among other things. everyone due to the global pandemic, but we have taken great pains to create a forum for meeting We hope you will find this event as stimulating and and discussion of the highest level and content. rewarding as the previous ones have been. So much so that, this year, in which we can meet face-to-face again, we are welcoming guests from My esteemed participants, welcome to this VIII public institutions from 11 countries in the region, as Forum and thank you very much for your interest and well as representatives of 10 companies in the field continued commitment to HTAi! of health technology. We are honored to have as our guests a representative of the Pan American Health Dr. Manuel A. Espinoza, MD MSc PhD Organization -PAHO, two international speakers and President four patient representatives, thus showing once HTAi Latin American Health Technology again our commitment to the end users of health Assessment Policy Forum technology innovations. 1

Welcome from the HTAi Latin Policy Forum Chair Welcome | Bienvenida Bienvenida del Presidente del Foro Latino de Políticas de HTAi Apreciadas y apreciados colegas, El tema elegido en esta ocasión, “Cómo los nuevos esquemas de acceso, incluyendo los acuerdos de Les damos la bienvenida al VIII Foro Latinoamericano riesgos compartidos, pueden contribuir a las decisiones de Políticas de Evaluación de Tecnología Sanitaria de cobertura”, ha sido seleccionado a partir de las (ETESA) de HTAi! preferencias y necesidades manifestadas por nuestros participantes en años anteriores. Como en años anteriores, nuestro Foro continúa ofreciendo un espacio de debate neutral e Por último, aprovechamos esta ocasión para independiente sobre temas de interés común agradecer formalmente a todos los oradores por para profesionales senior de instituciones públicas sus presentaciones y excelente predisposición y privadas en relación a la toma de decisiones como así también a los miembros del Comité estratégicas en el campo delas tecnologías médicas. Organizador de este Foro por sus contribuciones y direccionamiento en la ejecución del documento de Este año, contaremos con la presencia de invitados base, así como en el diseño de la agenda, entre otros. de instituciones públicas de 11 países de la región y también con representantes de 10 empresas del área Deseamos que encuentren este evento tan de tecnologías en salud. productivo como han sido los anteriores. Bienvenidas y bienvenidos, apreciados participantes Estamos complacidos de contar con la participación de este VIII Foro. ¡Muchas gracias por su de representantes de la Organización Panamericana interés y compromiso continuo con HTAi! de la Salud- PAHO y del Banco Interamericano de Desarrollo, así como con dos oradores internacionales Dr. Manuel A. Espinoza, MD MSc PhD y cuatro representantes de pacientes; lo que Presidente demuestra nuestro compromiso con los usuarios Foro Latinoamericano de Políticas de Evaluación de finales de las innovaciones tecnológicas en salud. Tecnología Sanitaria de HTAi 2

Welcome | Bienvenida COVID-19 TESTING OPTIONS FOR TRAVELLERS GENOSUR Av. Américo Vespucio 1292, Pudahuel, Región Metropolitana, Chile • PCR test base cost is $45 CDN results in less than 4 hours Booking is available through their website:   get.genosur.com/en/pcr_en_laboratorio Clinica Cellus Av. Presidente Kennedy 5757 Office 700 • Results in less than 12 hours base cost is $45 CDN Booking is available through their website:   www.viajeroslatam.cellus.cl Test Service • Results in less than 4 hours base cost is $80 CDN Booking is available through WhatsApp: +55 9 9062 0759 testservice.cl 3

OPCIONES DE PRUEBA DE Welcome | Bienvenida COVID-19 PARA VIAJEROS GENOSUR Av. Américo Vespucio 1292, Pudahuel, Región Metropolitana, Chile • Resultados en menos de 4 horas el costo base es de $45 CDN La reserva está disponible a través de su sitio web: get.genosur.com/en/pcr_en_laboratorio Clinica Cellus Av. Presidente Kennedy 5757 Office 700 • Resultados en menos de 12 horas el costo base es de $45 CDN La reserva está disponible a través de su sitio web:  www.viajeroslatam.cellus.cl Test Service • Resultados en menos de 4 horas el costo base es de $80 CDN La reserva está disponible a través de WhatsApp: +55 9 9062 0759 testservice.cl 4

Welcome | Bienvenida Sharing Compartiendo Information información HTAi would like to encourage Forum members to HTAi desea alentar a los miembros del Foro a share their thoughts and experiences on social media. compartir sus pensamientos y experiencias en las However, please keep in mind the HTAi Latin America redes sociales. Sin embargo, tenga en cuenta que el Policy Forum is held under the Chatham House Rule Foro de Políticas de América Latina HTAi se lleva a so neither the identity nor affiliation of the speaker(s), cabo bajo la regla de Chatham House, por lo que ni la nor that of any other participant, may be revealed. identidad ni la afiliación los orador(es), ni la de ningún otro participante, podrá ser revelada. Official hashtag: #2023LATAM Hashtag oficial: #2023LATAM Social media handles: Manejo de redes sociales: Facebook | @HTAiOrg Twitter | @HTAiOrg Facebook | @HTAiOrg LinkedIn | Health Technology Assessment Twitter | @HTAiOrg International (HTAi) LinkedIn | Evaluación Internacional de Tecnologías de la Salud (HTAi) Meeting Information Información de la reunión The 2023 HTAi Latin America Policy Forum will take place on August 13 – 15, 2023 in Santiago, Chile. El Foro de Políticas de América Latina HTAi 2023 se llevará a cabo del 13 al 15 de agosto de 2023 en Registration will take place from 8:30 a.m. to 9:00 a.m. Santiago de Chile. on Monday, August 15, 2023, outside The Arrayan Room in the Renaissance Santiago Hotel. La inscripción se realizará de 8:30 am a 9:00 am el lunes 15 de agosto de 2023, afuera de la Sala “El Arrayán” en TOPIC el Hotel Renaissance Santiago. The topic for the meeting is: ‘How new access schemes, including risk-sharing agreements, can contribute to TEMA coverage decisions’. El tema de la reunión es: ‘Cómo los nuevos esquemas de acceso, incluyendo los acuerdos de riesgos compartidos, pueden contribuir a las decisiones de cobertura’. 5

Networking Recepción Welcome | Bienvenida Reception de Redes D Bar D Bar • Located on the ground floor of the • Ubicado en la planta baja del Renaissane Renaissance Santiago Santiago Time: 18:00 onwards Hora: 18:00 en adelante Food and Beverages will be provided Alimentos y bebidas a disposición 6

Welcome | Bienvenida Social Dinner Cena Social Kitchen Club Kitchen Club Av. Pdte. Kennedy Lateral 7540 Av. Pdte. Kennedy Lateral 7540 7650618 Santiago, Vitacura 7650618 Santiago, Vitacura Región Metropolitana, Chile Región Metropolitana, Chile Time: 19:30 - 23:00 Hora: 19:30 - 23:00 We have booked a private coach from the Hemos reservado un autobús privado desde el Renais- Renaissance Santiago to the Kitchen Club, we sance Santiago hasta Kitchen Club, lepedimos que se ask that you join us in the hotel lobby at 19:15. una a nosotros en el vestíbulo del hotel a las 19:15. Please note the bus will leave the venue at 19:30. Tenga en cuenta que el autobús saldrá del lugar a las 19:30. goo.gl/maps/AQDbfMZuBtGrGod58 7

Meeting Hotel de Welcome | Bienvenida Hotel Reuniones Renaissance Santiago Hotel Renaissance Santiago Hotel Av. Pdte. Kennedy 4700, 7630454 Av. Pdte. Kennedy 4700, 7630454 Vitacura, Región Metropolitana, Chile Vitacura, Región Metropolitana, Chile Phone +56 2 2678 8888 Phone +56 2 2678 8888 Email:  [email protected] Correo electrónico: [email protected] Website: Sitio web: The Renaissance Santiago Hotel is one of the El Hotel Renaissance Santiago es uno de los first hotels in Santiago, Chile, with LEED® GOLD primeros hoteles en Santiago de Chile, con Certification and is immersed in Chile’s vibrant capital Certificación LEED® GOLD y está inmerso en la city and only 25 minutes from the airport. vibrante capital de Chile a solo 25 minutos del aeropuerto. The hotel rooms feature plush bedding, stylish décor and many feature floor-to-ceiling windows Las habitaciones del hotel cuentan con ropa de with stunning views of the Andes Mountains. Active cama lujosa, una decoración elegante y muchas travelers maintain their daily routine at the cuentan con ventanas del piso al techo con fitness center and outdoor pool. impresionantes vistas de la Cordillera de los Andes. Los viajeros activos mantienen su rutina diaria en el Check-in is available from 15:00 on your day of arrival gimnasio y la piscina al aire libre. to request an early check-in, please contact the hotel. Check-out is 12:00 on the day of departure. El check-in está disponible a partir de las 15:00 del día de su llegada. Para solicitar un check-in anticipado, póngase en contacto con el hotel. El check-out es a las 12:00 del día de salida. 8

LATIN AMERICA POLICY FORUM AGENDA August 13 - 15, 2023 | Santiago, Chile “How new access schemes, including risk-sharing agreements, can contribute to coverage decisions” Networking Activities: Sunday, August 13 | Welcome Reception | D Bar Monday, August 14 | Social Dinner | Kitchen Club

SUNDAY, AUGUST 13 Agenda 18:00 - 20:00 Welcome Reception D Bar | Renaissance Santiago MONDAY, AUGUST 14 7:30 - 8:30 Breakfast at leisure Catae Restaurant 8:30 - 9:00 Registration Terrace Olas 9:00 - 9:20 Welcome & Introduction Dr. Manuel Antonio Espinoza, 9:20 – 11:00 HTAi Latin America Policy Forum Chair, Chile 11:00 - 11:30 11:30 - 12:55 Rabia Sucu, HTAi President, Ukraine Shared Risk Agreements (Managed Entry Agreements) and their importance in Health Technology Assessment Processes MEA Overview (15 min) Héctor Castro (PAHO), Colombia MEA HTA Agencies Overview (15 min) Dr. Wija Oortwijn (Radboud University Medical Centre, HTAi Past President), Netherlands MEA NICE Overview (15 min) Pilar Pinilla-Dominguez (NICE), United [Virtual presentation] Kingdom MEA Industry Overview (15 min) Diego Guarin (MSD), United States Q&A All participants Background Paper Summary Sebastián García Martí, Coordinator of Assessment of Health Technologies and Health Economics (IECS), Argentina Coffee Break Networking Local Situation Moderator: Héctor Castro (PAHO), Colombia Experience in MEA in Uruguay (10 min) Graciela Fernandez (National Resource Fund), Uruguay Experience in MEA in Argentina Natalia Messina, High Cost and Special (10 min) Medicine (Health Minister Argentina), Argentina 10

Agenda MONDAY, AUGUST 14 12:55 - 13:10 Experience in MEA in Brazil (10 min) Luciene Bonan (CONITEC- 13:10 - 15:00 Comissão Nacional de Incorporação de 15:00 - 16:45 Patient and User Perspective (15 min) Tecnologias no Sistema Único de Q&A Saúde), Brazil 16:45 - 17:15 Presentation and Instructions for Alejandro Andrade (FECHER), Chile 17:15 - 18:15 Breakout Groups All participants Andrés Pichon-Riviere, Director 18:15 - 18:30 (IECS-Institute for Clinical Effectiveness 18:30 - 19:15 and Health Policy), Argentina 19:15 – 19:30 19:30 - 23:00 Lunch Networking Breakout Groups – Activity 1 All participants Discussion activity and group work on the current situation of the region (Challenges) Coffee Break Networking Breakout Groups Report Back Moderator: Dr. Manuel Antonio (30 minutes) Espinoza, HTAi Latin America Policy Forum Chair, Chile Plenary Discussion (30 minutes) Breakout session rapporteurs Social Dinner Logistics All participants Dr. Manuel Antonio Espinoza, HTAi Latin America Policy Forum Chair, Chile Break All participants Ground transportation to All participants Social Dinner venue Social Dinner Kitchen Club 11

TUESDAY, AUGUST 15 Agenda 7:45 - 8:45 Breakfast at leisure Catae Restaurant 8:45 - 9:00 Registration Dr. Manuel Antonio Espinoza, 9:00 - 9:15 Key themes and takeaways from HTAi Latin America Policy Forum Chair, the first day of the Forum Chile 9:15 - 11:00 Presentation and Instructions Andrés Pichon-Riviere, HTAi Latin 11:00 - 11:30 for Breakout Groups America Policy Forum Scientific 11:30 - 12:00 Secretary, Argentina Breakout Groups – Activity 2 All participants 12:00 - 12:30 Identifying opportunities for the 12:30 - 13:00 implementation of MAE in Latin America 13:00 - 13:15 13:15 - 14:15 Coffee Break Networking Breakout Groups Report Back Moderator: Dr. Manuel Antonio (30 minutes) Espinoza, HTAi Latin America Policy Forum Chair, Chile Representative of each group Plenary Discussion (30 minutes) All participants Contribution of the HTAi Latin America Policy Forum in Latin America Health Policies Statement of the HTAi Policy Forum – Dr. Manuel Antonio Espinoza, Santiago (15 min) HTAi Latin America Policy Forum Chair, Promoting the active participation of Chile patient representatives in HTA in Eva Maria Ruiz de Castilla (LAPA-Latin LATAM: Opportunities from LATAM America Patients Academy), United HTAi PF (15 min) States Possible topics for future Forums – Dr. Federico Augustovski Survey (IECS-Institute for Clinical Effectiveness and Health Policy), Argentina Lunch & Closing Forum Networking 12

FORO DE POLÍTICAS EN EVALUACIÓN DE TECNOLOGÍAS SANITARIAS EN LATINO AMÉRICA AGENDA 13 – 15 de agosto, 2023 | Santiago de Chile “Cómo los nuevos esquemas de acceso, incluyendo los acuerdos de riesgos compartidos, pueden contribuir a las decisiones de cobertura” Actividades de intercambio: Domingo, 13 de agosto | Recepción de bienvenida | D Bar Lunes, 14 de agosto | Cena Social | Kitchen Club

DOMINGO 13 DE AGOSTO Agenda 18:00 - 20:00 Recepción de bienvenida D Bar | Renaissance Santiago LUNES 14 DE AGOSTO 7:30 - 8:30 Desayuno pausado Catae Restaurant 8:30 - 9:00 9:00 - 9:20 Recepción y registro de participantes Terrace Olas 9:20 – 11:00 Bienvenida e introducción Dr. Manuel Antonio Espinoza, 11:00 - 11:30 presidente Foro Latinoamericano de 11:30 - 12:55 Políticas de Evaluación de Tecnologías Sanitarias de HTAi, Chile Rabia Sucu, presidente HTAi, Ucrania Esquemas de Acceso (EA) y su importancia en los procesos de Evaluación de Tecnologías Sanitarias Contextualización de los EA Héctor Castro (OPS), Colombia EA Perspectiva de la Agencia en Dr. Wija Oortwijn (Radboud University Evaluación de las Tecnologías Sanitarias Medical Centre, Presidente anterior de HTAi), Países Bajos EA Perspectiva de una agencia Pilar Pinilla-Dominguez, directora Internacional Asociada (NICE), Estados Unidos [Presentación virtual] EA Perspectiva de la Industria Diego Guarin (MSD), Estados Unidos Preguntas y respuestas Todos los participantes Documento base - Resumen Sebastián García Martí, Coordinador de Evaluación de Tecnologías Sanitarias y Economía de la Salud (IECS), Argentina Pausa para el café Intercambio Situación local Moderador: Héctor Castro (OPS), Colombia Experiencias de EA en Uruguay Graciela Fernandez (Fondo Nacional de Recursos), Uruguay Experiencias de EA en Argentina Natalia Messina, Dirección de medicamentos especiales y de alto precio (Ministerio De Salud República 14 Argentina), Argentina

Agenda LUNES 14 DE AGOSTO Experiencias de EA en Brasil Luciene Bonan (CONITEC-Comisión Nacional de Incorporación de Tecnologías en el Sistema de Salud), Brasil Perspectiva de los pacientes y usuarios Alejandro Andrade, Federación Chilena de Enfermedades Raras (FECHER), Chile Preguntas y respuestas Todos los participantes 12:55 - 13:10 Presentación e instrucciones para Andrés Pichon-Riviere, Director 13:10 - 15:00 los grupos de discusión (IECS-Instituto de Efectividad Clinica 15:00 - 16:45 y Sanitaria), Argentina 16:45 - 17:15 Almuerzo Intercambio 17:15 - 18:15 Grupos de discusión - Actividad 1 18:15 - 18:30 Actividad de intercambio y análisis de Todos los participantes 18:30 - 19:15 situación actual en la región (desafíos) 19:15 – 19:30 19:30 - 23:00 Pausa para el café Intercambio Presentación de los grupos Moderador: Dr. Manuel Antonio de discusión (30 minutos) Espinoza, presidente Foro Latinoamericano de Políticas de Evalu- ación de Tecnologías Sanitarias de HTAi, Chile Oradores de grupos de discusión Discusión plenaria (30 minutos) Todos los participantes Logística de la cena social Dr. Manuel Antonio Espinoza, presidente Foro Latinoamericano de Descanso Políticas de Evaluación de Tecnologías Traslado a la locación de la Sanitarias de HTAi, Chile Cena Social Todos los participantes Cena Social Todos los participantes Kitchen Club 15

MARTES 15 DE AGOSTO Agenda 7:45 - 8:45 Desayuno pausado Catae Restaurant 8:45 - 9:00 Registro de participantes 9:00 - 9:15 Temas centrales y recapitulación Dr. Manuel Antonio Espinoza, desde el primer día del Foro presidente Foro Latinoamericano de 9:15 - 11:00 Políticas de Evaluación de Tecnologías 11:00 - 11:30 Presentación e instrucciones para Sanitarias de HTAi, Chile 11:30 - 12:00 el trabajo en grupos de discusión Andrés Pichon-Riviere, Director (IECS-Instituto de Efectividad Clínica y 12:00 - 12:30 Grupos de discusión - Actividad 2 Sanitaria), Argentina 12:30 - 13:00 Identificando oportunidades para la implementación de EA en Todos los participantes 13:00 - 13:15 Latinoamérica 13:15 - 14:15 Pausa para el café Intercambio Presentación de los grupos Moderador Dr. Manuel Antonio de discusión Espinoza, presidente Foro Latinoamer- icano de Políticas de Evaluación de Tecnologías Sanitarias de HTAi, Chile Un representante de cada grupo de discusión Sesión plenaria Todos los participantes Contribución del Foro Latinoamericano de HTAi a las políticas públicas de Latinoamérica Acuerdos del Foro de Políticas en Dr. Manuel Antonio Espinoza, Evaluación de Tecnologías Sanitarias en presidente Foro Latinoamericano de Latinoamérica - Santiago (15 minutos) Políticas de Evaluación de Tecnologías Sanitarias de HTAi, Chile Promoviendo la participación activa Eva Maria Ruiz de Castilla (LAPA-Latin de los representantes de pacientes en America Patients Academy), Estados Evaluaciones de Tecnologías Sanitarias Unidos en Latinoamérica: oportunidades a Dr. Federico Augustovski partir del Foro (15 minutos) (IECS-Instituto de Efectividad Clínica Posibles tópicos para futuros y Sanitaria), Argentina Foros – Encuesta Almuerzo y cierre del foro Intercambio 16

Background Paper | Documento de base HTAI 2023 LATIN AMERICA HEALTH TECHNOLOGY ASSESSMENT POLICY FORUM BACKGROUND PAPER How new access schemes, including risk-sharing agreements, can contribute to coverage decisions VIII Latin America Health Technology Assessment Policy Forum (Latam Policy Forum). Chile, August 2023. This document was prepared by Sebastián García Martí, Andrea Alcaraz, Lucas Perelli, Federico Augustovski, and Andrés Pichon Riviere Institute of Clinical Effectiveness and Health Policy (IECS) - Argentina With acknowledgements to Manuel Espinoza, President of the 2023 HTAi Latin American Policy Forum and the members of the Organizing Committee: William Dorling (Pfizer), Felipe Vera (Ministry of Health, Chile), Luciene Bonan (Ministry of Health, Brazil), Adriana Maria Robayo (Institute of Health Technology Assessment, Colombia), Graciela Fernandez (National Resources Fund, Uruguay), Fernanda Laranjeira (Medtronic), Diego Guarín (MSD), and Alicia Granados (Sanofi) for their comments and suggestions in the preparation of this document. 17

OVERVIEW OF THE 2023 LATAM POLICY FORUM Background Paper | Documento de base Managed entry agreements (MEAs) encompass different types of agreements between stakeholders such as drug manufacturers, payers, and patients to share the risks and benefits associated with the reimbursement of a particular treatment. These agreements are tools that are increasingly to address challenges in access to innovative and high-cost therapies. In the Spanish language, the terminology around these agreements can sometimes have different meanings, and there is also the term “risk-sharing agreements” (RSAs) that can be used interchangeably. The potential utility of such agreements in Latin America will be explored, with consideration to the challenges in access to medicines, health system financial sustainability, and the need to guarantee access to innovative and high-quality treatments. A description of how these agreements work will be presented along with examples of their implementation in the region and elsewhere in the world. This background paper provides information to decision makers, policy makers, and technology manufacturers to enable greater participation of participants in the 2023 Latam Policy Forum to be held in Chile. Background Document Table of Contents 1. Introduction 2. Background 3. Managed entry agreements a. Definition and taxonomy b. Difference between financial- and performance-based agreements c. Description of recent uses 4. Evaluation of potential utility 5. Potential for future use 6. International and regional experiences 7. References 18

Background Paper | Documento de base 1. INTRODUCTION Both healthcare payers and technology manufacturers have the shared interest to enable rapid access to technologies after they receive market authorization. However, in some situations there is uncertainty about the true benefit of technology or the health system budget impact of a technology. To address such situations of uncertainty, managed entry agreements (MEA) can be used, also known as risk-sharing agreements, to establish a contract between the manufacturers and payers that allow risks associated with this uncertainty (about clinical benefit or budget impact) to facilitate technology coverage.1 These agreements can help mitigate the consequences of making coverage decisions when there is uncertainty about the effects of a new treatment. Making inappropriate decisions can result in poor health outcomes, waste resources, and reduce the credibility of the decision-making processes. These agreements can be used to set payment schedules and reimbursement terms that are fair and equitable to healthcare payers and providers as well as technology manufacturers, while ensuring access to quality care. These types of agreements have been used for those technologies with the potential for high budget impact in reimbursement where the uncertainty (either budgetary or clinical performance) can be reduced. This type of agreement aims to “share” the risks associated with the reimbursement of technologies between the payer and manufacturer in situations where, due to the characteristics of the particular pathology, there is elevated uncertainty about the evidence quality or the budget impact after adoption. In other words, they represent a strategy to share risk between the manufacturer of drugs, devices or diagnostic tests, and the payers, whether they are health systems, social security providers or private insurers. These agreements are used to provide access to innovative technologies and, in some cases reduce the cost of treatment, mainly in situations where there is insufficient certainty about outcomes or whether the technology will have positive results in the real world similar to what is shown in clinical studies. The objective of the eighth annual Latin American Health Technology Assessment (Latam) Policy Forum will be to consider the potential utility of using managed entry agreements (MEA) including risk sharing agreements (RSA) in the reimbursement of health technologies. The Forum will analyze the characteristics of these agreements including the barriers and facilitators that different stakeholders encounter in their use, and to define a series of key principles and actions to guide choices in their implementation. What is health technology assessment (HTA)? Health technology assessment (HTA) is a multidisciplinary process that uses explicit methods to determine the value of a health technology at different points in its lifecycle.2 The purpose is to inform decision-making in order to promote an equitable, efficient, and high-quality health system. The information is used by health systems to make resource allocation decisions such as whether or not to grant coverage to a particular health technology or to incorporate it into a benefits package. 17 1 Garrison, L. et al. (2013), “Performance-Based Risk-Sharing Arrangements—Good Practices for Design, Implementation, and Evaluation: Report of the ISPOR Good Practices for Performance-Based Risk-Sharing Arrangements Task Force”, Value in Health, Vol. 16/5, pp. 703-719, http://dx.doi. org/10.1016/j.jval.2013.04.011. 2 O’Rourke B, Oortwijn W, Schuller T; International Joint Task Group. The new definition of health technology assessment: A milestone in international collaboration. Int J Technol Assess Health Care. 2020 Jun;36(3):187-190.

Today health technologies are an indispensable part of health systems and their use has increased over Background Paper | Documento de base recent decades. The introduction of new technologies has generally brought significant benefits in terms of safety, illness prevention, improvements in health and quality of life, or a reduction in adverse effects. However, in situations of limited resources, ensuring the appropriate reimbursement and diffusion of technologies has become a challenge and, in some cases, a serious problem. The rapid pace of new technologies coming to market and the increase in the volume of available evidence are currently faced by all health systems. The delivery of health services involves making decisions about: which interventions are to be made available (and implicitly or explicitly which are not); how the health system is to be organized; who will pay for these interventions; and, how they should be provided and by whom. The challenge is to achieve adequate health outcomes with the resources available, having also considered the social values, expectations, and demands of the population. Many countries have committed to achieving universal health coverage (UHC) for their population, which is one of the objectives prioritized by the World Health Organization (WHO). The WHO emphasizes that to achieve UHC, a strategy for the prioritization of interventions is essential, and that this is to be based on the best available evidence and conducted in a deliberative process that takes into account social values.3 4 In this endeavour, healthcare decision-makers have increasingly needed reliable and detailed information that enables them to make transparent and legitimate decisions when setting priorities, with a view to maximizing the benefits realized through limited budgets. The development and growth of HTA mirrors this increasing demand for robust and transparent information to support decisions about the development, reimbursement, and diffusion of health technologies.5 HTA began in the 1970s in light of the growing concern about the diffusion of new and expensive health technologies and the limitations of health systems to finance their use. The discipline of HTA grew from these beginnings over forty years ago to become today a multidisciplinary specialty with the purpose of retrieving and synthesizing available evidence to support healthcare decision- makers, professionals, and patients to understand the relative value of technologies. The development of HTA has been especially notable in the last 20 years and it is now an essential component of health systems in many countries. In the Latin American and Caribbean (LA) region several such initiatives have emerged. Argentina, Brazil, Colombia, Chile, Mexico and Uruguay have HTA agencies that are members of INAHTA (acronym for the International Network of HTA Agencies), and several Latin American countries use HTA, to different a extent, to support resource allocation decision-making. Most of these initiatives in the region are grouped in RedETSA, the health technology assessment network of Latin America (http://redetsa.org/), coordinated by the Pan American Health Organization (PAHO). HTA can be a very useful tool for decision-makers. However, if it is not conducted and used appropriately, it runs the risk of poorly informing decisions that can lead to inefficient resource allocation by: reimbursing interventions of little or no benefit; impeding or delaying patient access to useful health technologies; exposing patients to unnecessary risks; and, sending the wrong messages to technology manufacturers, among others.6 Furthermore, HTA is not purely a technical exercise and the decision-making process must take into account increasingly broad dimensions. The decisions 3 Terwindt F, Rajan D, Soucat A. Priority-setting for national health policies, strategies and plans. In: Schmets G, Rajan D, Kadandale S, eds. Strategiz- ing national health in the 21st century: a handbook: World Health Organization (WHO); 2015:71 4 World Health Organization (WHO). Making fair choices on the path to universal health coverage. Final report of the WHO Consultative Group on Equity and Universal Health Coverage 2014: http://apps.who.int/iris/bitstream/10665/112671/1/9789241507158_eng.pdf?ua=1. Accessed 11- 3-2016 5 Gabbay J, Walley T. Introducing new health interventions. BMJ. 2006;332(7533):64-65. 6 Wilsdon T, Serota A. A comparative analysis of the role and impact of health technology assessment. London:UK: Charles River Associates; 2011. http://www.phrma.org/sites/default/files/pdf/hta_final_comparison_report_13_may_2011_stc1.pdf 18

Background Paper | Documento de base made based on the HTA process have the potential to affect a large number of people and institutions and therefore a series of basic principles have been proposed for HTA. These principles include aspects such as transparency in the HTA implementation and decision-making processes; the involvement of relevant stakeholders; the presence of explicit mechanisms to decide which technologies to be assessed; and, the existence of a clear link between the assessment and decision-making.7 8 9 Many of these aspects were addressed in previous years of the Latam Policy Forum. 10 11 12 13 14 15 2. BACKGROUND AND OBJECTIVES OF THE FORUM The Health Technology Assessment Policy Forum was founded in 2004 by Health Technology Assessment International (HTAi) to provide a neutral space for strategic discussions on the development and current state of HTA, along with related implications for health systems, industry, patients, and other stakeholders. It brings together representatives of three main groups: 1) decision makers responsible for coverage, reimbursement, and pricing of drugs and devices used in the health system; 2) organizations that carry out HTA in support of these decisions; and, 3) biomedical companies that produce technologies. The main Policy Forum has been operating for 17 years with a focus on Europe and the United States; and for the past 10 years, a Policy Forum has been running in Asia. In 2016, the Policy Forum began in Latin America, with 2023 being the eighth Latam Policy Forum conducted. An Organizing Committee composed of the Forum President and representatives of the participating institutions (three representatives from the public sector and three from technology manufacturers) developed the topic, agenda, and logistical details of the Forum. The Institute of Clinical Effectiveness and Health Policy in Argentina (IECS – www.iecs.org.ar) served as the Scientific Secretariat. The process to select the topic of this eighth Forum began during the previous year’s event and included the following steps: 1. A list of topics was prepared based on suggestions from the members of the Latam Policy Forum, and a vote was held during the closing of the 2022 Forum to identify the highest priority topics for 2023 based on this list. 2. The prioritized topics were sent to the Organizing Committee for their comments/suggestions. 3. The final topic was selected through a deliberative process by the Organizing Committee. As a result of this process, the topic selected for the Latam Policy Forum was, “How can new access schemes, including risk sharing agreements, contribute to coverage decisions?”. 19 7 Daniels N, Sabin J. Setting limits fairly: learning to share resources for health. 2nd ed. New York: Oxford University Press; 2008 8 Drummond MF, Schwartz JS, Jönsson B, Luce BR, Neumann PJ, Siebert U, Sullivan SD. Key principles for the improved conduct of health technology assessments for resource allocation decisions. Int J Technol Assess Health Care. 2008. Summer;24(3):244-58; discussion 362-8 9 Pichon-Riviere A, Augustovski F, Rubinstein A, Martí SG, Sullivan SD, Drummond MF. Health technology assessment for resource allocation decisions: Are key principles relevant for Latin America? Int J Technol Assess Health Care. 2010 Oct;26(4):421-7 10 Pichon-Riviere A, Soto NC, Augustovski FA, García Martí S, Sampietro-Colom L. Health techonolgy assessment for decision making in Latin Ameri- ca: good practice principles. Int J Technol Assess Health Care, 34:3 (2018), 1-7 11 Pichon-Riviere A, Soto NC, Augustovski FA, Sampietro-Colom L. Stakeholder involvement in health technology assessment process in Latin Ameri- ca. Int J Technol Assess Health Care, 34:3 (2018), 1-6 12 Pichon-Riviere A, GarciaMarti S, Oortwijn W, Augustovski F, SampietroColom L (2019). Defining the Value of Health Technologies in Latin America: Developments in Value Frameworks to Inform the Allocation of Healthcare Resources. International Journal of Technology Assessment in Health Care 35, 64–68 13 Pichon-Riviere A, Augustovski F, García Martí S, Alfie V, Sampietro-Colom L (2020). The link between health technology assessment and decision making for the allocation of health resources in Latin America. International Journal of Technology Assessment in Health Care 36, 173–178 14 Pichon-Riviere A, Augustovski F, García Martí S, Alcaraz A, Alfie V, Sampietro-Colom L (2021). Identification and selection of health technologies for assessment by agencies in support of reimbursement decisions in Latin America. International Journal of Technology Assessment in Health Care 1–8 15 Alcaraz A, Pichon-Riviere A, García-Martí S, Alfie V, Augustovski F, Castro H. Deliberative processes in decision making informed by health technol- ogy assessment in Latin America. Int J Technol Assess Health Care. 2022 Dec 16;38(1):e86.

This eighth edition of the Latam Policy Forum follows from the previous seven. The first Forum was Background Paper | Documento de base held in Costa Rica in 2016 where the good practice principles in the application of HTA in decision- making in Latin America were discussed. During this Forum the principles prioritized as most relevant to promote the application of HTA in the Latin American region were: • Transparency in the HTA processes and communication of HTA results • Involvement of relevant stakeholders in the HTA process • Existence of mechanisms for appeal • Existence of clear mechanisms for establishing HTA priorities • Existence of a clear link between HTA and decision making The 2017 Latam Policy Forum was held in Lima, with the central theme being the involvement of different stakeholders in the HTA process, which was identified as a priority topic during the 2016 Forum. In 2018, the Forum was held in Montevideo where HTA value frameworks were discussed. In 2019, the Forum went to Buenos Aires where the topic was to look at the relationship between HTA and decision making. During the years of the Covid-19 pandemic, the Forum was conducted online, and in 2020 the Forum examined the mechanisms used by HTA agencies to the prioritize topics for assessment, and in 2021 they discussed the role of deliberative processes in HTA. In 2022, the Forum returned to being in-person and that year it was held in Brasilia on the topic of the use of real-world evidence in the HTA process. (The results of discussions held during the most recent five Latam Policy Forums are available in a series of publications: Pichon-Riviere et al. 2018-2022). The main objectives of the eighth Latam Policy Forum are to: • Understand the current state of MEA/RSA use in HTA and reimbursement processes in Latin America • Explore the benefits and limitations/barriers/risks to using MEA/RSA along with opportunities for their implementation in the region. • Discuss and identify the main aspects in the regional context that should be taken into account when implementing MEA/RSA, as well as good practice principles for their conduct. • Consider the potential to apply different models used elsewhere in the world to Latin American health systems, and to create a set of recommendations to guide the implementation of MEA/ RSA related to HTA in the region. The objective of this background document is to provide information as a starting point for the discussions that will take place in the HTAi 2023 Latin America Policy Forum that will take place in- person on 14 and 15 August in Santiago, Chile. The information is derived from a literature search focused on MEA/RSAs and HTA and from the review of agency and health system websites. 20

Background Paper | Documento de base 3. MANAGED ENTRY AGREEMENTS a. Definition and Taxonomy There are several varieties of MEA with no standard classification that encompasses all types of agreements. However, two main categories can be identified: financial-based agreements and those based on health outcomes.16 Both aim to share risk between the payer and the manufacturer in conditions of uncertainty regarding technology reimbursement. However, they address different areas of uncertainty: financial agreements aim to reduce uncertainty about the budget impact of acquiring new health technologies, while performance-based agreements seek to reduce uncertainty regarding the effectiveness and cost-effectiveness (or performance) of innovations.17 Financial-based agreements (FBAs) aim to manage uncertainty around the budget impact of a new technology. They are not linked to clinical outcomes and do not require health outcomes data to be analyzed. FBAs are contractual agreements that may establish the price, discounts, or reimbursement levels along with other terms and conditions associated with the procurement and/or use of a health technology. Agreements based on clinical outcomes (COAs) are established between a payer and a manufacturer to set prices, discounts, or reimbursement levels for a product based on the achievement of predefined clinical outcome targets. They require that clinical outcomes be analyzed and monitored for patients involved in the agreement. They also have a financial objective, but this is specifically related to the clinical outcomes. Table 1 presents the different types of agreements organized according to their taxonomy. Table 1. Taxonomy of agreement types FINANCIAL-BASED AGREEMENTS Discounts Price/volume agreements Budget capping (subscription) agreements Utilization capping agreements CLINICAL OUTCOME-BASED AGREEMENTS Performance-based agreements Coverage with evidence development agreements 21 16 Carlson, J. et al. (2010), “Linking payment to health outcomes: A taxonomy and examination of Health Policy, Vol. 96/3, pp. 179-190, http://dx. doi.org/10.1016/j.healthpol.2010.02.005. 17 Wenzl, M. and S. Chapman (2019), “Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward”, OECD Health Working Papers, No. 115, OECD Publishing, Paris, https://doi. org/10.1787/6e5e4c0f-en.

Financial-Based Agreements Background Paper | Documento de base Described below are four commonly used types of financial-based agreements. Discounts. It should be noted that this type of agreement does not correspond to what is typically considered risk sharing. While it could be argued that a discount is the manufacturer assuming some of the risk, since this is applied in situations of certainty, it does not constitute a risk allocation in itself. The redistribution of risk can be applied to costs that have already been discounted. However, there are the simplest and most common type of agreement, they involve providing a price discount for the drug or other health technology based on various factors. For example, there may be a discount based on the volume of product purchased or based on the duration of the contract. Price/volume agreements are based on a sliding scale of prices for the drug or health product based on the volume of sales. For example, if a certain number of units is purchased, the price per unit will be lower. This type of agreement is beneficial for the supplier, since there is an incentive to stimulate increased sales of the product, and also for the buyer, who can obtain a lower price per unit if certain purchase levels are reached. Budget capping agreements are where a pre-established spending limit is set for a specific drug or health product. The objective is to ensure that the budget allocated to a technology does not exceed a certain level, which can help control health system costs. Sometimes this type of agreement is called a subscription model (Netflix model) since the producer provides the required number of treatments for a fixed amount of money. Utilization capping agreements involve setting a limit on the number of patients or doses per patient to receive a drug or health technology. The goal here is to limit the use of the technology only to patients who are expected to benefit from it, i.e., those within its approved indication. In summary, FBAs are useful tools to control costs and promote access to health technologies. The four types of agreements described above are commonly used to control spending in clinical practice and they are much easier to implement compared to clinical outcomes-based agreements. Clinical Outcomes-Based Agreements Clinical outcomes-based agreements can be classified as follows: A. Performance-based agreements: In these agreements, reimbursement is linked to the effectiveness of the drug or technology in the real world, meaning that specified criteria must be met for full or partial reimbursement. The goal is to assess the value of technology in a real- world healthcare environment. This type of arrangement can be beneficial to both the payer and manufacturer, as the payer only pays for drugs that work, while the producer receives greater financial certainty. There are different variations of this type of agreement. They can be based on the process of care, whereby reimbursement is specified a priori and depends on the clinical decision-making process. For example, payment can be linked to provider adherence to clinical guidelines or selection of individual patients based on a biomarker, such as a genetic test. In other cases, agreements can be based on outcomes where reimbursement occurs a posteriori through measuring intermediate or clinical endpoints. These may include measures of efficacy, safety, and/or cost-effectiveness. An “outcomes guarantee” can be implemented, for example, the manufacturer agrees to provide a partial or full refund if the drug or technology does not perform as expected. In other situations, the “conditional continuation of treatment” is negotiated, that is, the payment for the continued use of the therapy is made based on the patient outcomes realized. 22

Background Paper | Documento de base Regarding the monitoring of clinical endpoints, patient risk-sharing agreements can be implemented. In these agreements, patients take and active role in the management of their disease and the monitoring of their response to treatment. The agreement may include incentives for the patient to adhere to the treatment regimen and to report outcomes to healthcare providers. The agreement may also include a partial or full refund if the patient does not respond adequately to the treatment. Healthcare provider risk sharing agreements, on the other hand, involve healthcare providers in the financial risk of treatment. In these cases, the manufacturer agrees to provide the therapy at a reduced price or with a partial refund, and healthcare providers agree to monitor and report treatment outcomes. If these outcomes are not as expected, the manufacturer provides an additional refund. B. Coverage with evidence development (CED) agreements: These agreements – the most complex to implement - provide coverage for a new drug or medical technology while additional clinical studies are carried out to confirm the product’s effectiveness and safety. The goal is to allow patient access to the technology while additional data is collected. These agreements link payment or reimbursement at the population level with prospective data collection from individual patients. The agreement may affect all patients eligible to receive the technology (called ‘only with research’ agreements) or only those patients who are voluntarily included in a clinical trial (called ‘only in research’ agreements). These agreements provide coverage for a drug or technology for specific patients based on certain conditions. For example, coverage may be limited to patients with certain characteristics or at certain stages of the disease. Coverage is reviewed regularly and may change based on the results of additional clinical trials. Presented below are some examples of the various agreement types:18 Financial-based agreements • Budget limit agreements Antivirals for Hepatitis C in Australia (since 2015). The government allocated an annual budget for these drugs and above this budget limit the technology manufacturer reimbursed the total cost. • Utilization limit agreements Lenalidomide for the treatment of myelodysplastic syndromes in the UK. The government pays for up to 26 cycles of treatment, and for those patients who require more than 26 cycles, these are provided by the technology manufacturer at no cost. Clinical outcome-based agreements • Reimbursement agreements linked to outcomes (payment by results) Alfaglucosidada Alfa for Pompe disease with late onset in Estonia. Payment is only made to those patients with a positive outcome confirmed by a panel of 4 specialist doctors. • Coverage with evidence development agreements Axicabtagene ciloleucel (Yescarta®) for B-cell lymphoma in England. The drug is covered by the Cancer Drug Fund (CDF) on the condition of generating more evidence of survival estimates. The evidence includes a phase II trial and the creation of a cancer registry. At the end of the agreement, the drug is reassessed and if there is insufficient evidence or the drug is deemed not to be clinically or economically effective, it may be removed from the CDF and no longer available from the NHS. In such a case, patients will continue to receive the medication but it must be paid for by the manufacturer until the prescribing physician deems discontinuation of therapy appropriate. 23 18 Wenzl, M. and S. Chapman (2019), “Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward”, OECD Health Working Papers, No. 115, OECD Publishing, Paris, https://doi. org/10.1787/6e5e4c0f-en.

b. Differences between financial-based and clinical outcomes-based Background Paper | Documento de base agreements When to choose a financial-based or clinical outcomes-based agreement The main difference between financial- and performance-based agreements is their focus. Financial agreements aim to share uncertainty about the financial risk and how a treatment will be paid for to permit health systems to more precisely manage their budgets. On the other hand, performance- based agreements address the clinical effectiveness of a therapy and how the quality of patient care can be improved. Agreements based on financial results are easier to implement than agreements based on clinical outcomes as they require less data collection and are generally less difficult to monitor. The choice of using a risk agreement based on clinical outcomes (performance) or a financial agreement will depend on the specific objective, the uncertainty of clinical information, and the cost of the technology. Risk sharing agreements based on clinical outcomes are used when clinical or health outcomes are unclear or uncertain, and the intent is to share the risk between the manufacturer and the payer. These agreements are generally used for new or innovative products, or in situations where outcomes are unpredictable. Financial agreements, on the other hand, are used to achieve specific savings or cost management objectives. They are often used for products that have a known history health and clinical outcomes. The choice between a risk sharing agreement based on clinical outcomes and a financial agreement will depend on the specific objectives to be achieved, as well as the nature and history of the drug or treatment in question. 3.3 Description of recent uses In 2019, Castro et al. published a literature review of managed entry agreements.19 Of the total found (n=285), 95% had been implemented in high-income countries (23 European countries, 6 Asian countries, 2 North American countries, 2 in Oceania and 1 in Africa). Financial-based agreements were more frequent than those based on clinical outcomes (50.2% vs. 44.9%, respectively). FBAs were the most common worldwide, while PBAs were most common in North America. This is consistent with other investigations into the different types of agreements utilized, where financial agreements are generally more frequent than those based on clinical outcomes.20 21 One example of a FBA is used by the United Kingdom’s National Institute for Health and Care Excellence (NICE), which negotiates with manufacturers to achieve acceptable levels of cost- effectiveness for the drugs that are covered.22 23 The incremental cost-effectiveness ratio (ICER) range 19 Castro, Hector & Malpica-Llanos, Tanya & Musila, Ruth & Konduri, Niranjan & Amaris, Ana & Sullivan, Jennifer & Gilmartin, Colin. (2019). Sharing 24 knowledge for policy action in low- and middle-income countries: A literature review of managed entry agreements. Medicine Access Point of Care. 3. 239920261983424. 10.1177/2399202619834246. 20 Ferrario, A. and P. Kanavos (2013), Managed entry agreements for pharmaceuticals: The European experience, EMiNet, Brussels. 21 Wenzl, M. and S. Chapman (2019), “Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward”, OECD Health Working Papers, No. 115, OECD Publishing, Paris. 22 Toumi, M., & Jarosławski, S. (2022). Managed Entry Agreements and Funding for Expensive Therapies. CRC Press. 23 Managed Access: Our Programmes. https://www.nice.org.uk/about/what-we-do/our-programmes/managed-access

Background Paper | Documento de base generally considered acceptable by NICE is £20,000-30,000 per quality-adjusted life year (QALY) gained and up to £51,000/QALY gained for end-of-life treatments. A much higher ICER range of £100,000- £300,000 was introduced in 2017 for ultra-orphan drugs that are assessed through the Highly Specialized Treatments pathway. NICE has patient access schemes that consist of simple discounts or trade agreements based on performance or on evidence generation. The discount range negotiated by NICE is typically between 30% and 60%, with most discounts being between the 45% to 50% range. Common situations where NICE would sign such agreements include where there is a lack of proven cost-effectiveness due to uncertainty of clinical or other data for economic analysis, as well as uncertainty related to relative efficacy and the need to collect more evidence on long-term outcomes and adverse effects of treatment. For cell and gene therapy (known as highly specialized therapied (HST)) drugs agreements are based on financial and clinical assessment, as cost-effectiveness is always uncertain due to data limitations encountered in rare diseases. In addition to the Cancer Drugs Fund negotiations, England’s National Health Service (NHS) is involved in confidential rebate negotiations with manufacturers leading to further cost savings. An example of an outcomes-based agreement implemented by NICE was for Hepatitis C drugs (Glecaprevir/Pibrentasvir Maviret® and Sofosbuvir Sovaldi®).24 Due to their high cost, the NHS England was required to limit access to direct-acting antiviral drugs only to selected patients, despite a positive recommendation from NICE. To manage public pressure and improve patient access, in 2017 the NHS England signed a clinical-outcomes based agreement with manufacturers. Under this agreement, the NHS would be reimbursed by manufacturers for the cost of treatment for those patients who completed their treatment but did not achieve a cure (sustained virologic response). Patients were followed in a hepatitis C registry to monitor treatment uptake and outcomes so reimbursement could be calculated. Another example from NICE relates to Spinraza® (Nusinersen) for spinal muscular atrophy (SMA) where a coverage with evidence development (CED) agreement was used. In 2019, NICE raised several concerns in the assessment of Spinraza related to the collection of clinical data and resource utilization.25 A five-year CED agreement was signed with the manufacturer that included a minimum of three years of data collection. The final reimbursement was agreed to be done in the fifth year of the CED scheme. Various endpoints for the CED agreement were collected from different sources: ongoing studies, some registries such as SMA REACH UK, the NHS Blueteq system used in the UK for high- cost medicines, and ongoing patient-reported outcomes. Data was analyzed twice a year according to a plan developed by the manufacturer, with the data collection and analysis costs borne by the manufacturer. This scheme is still ongoing. 3.4 EVALUATION OF POTENTIAL UTILITY MEA can improve access to therapies by increasing the likelihood of reimbursement when there is uncertainty related to efficacy or cost-effectiveness. They can also increase the time to make a final funding decision if they are very complex or expensive. In 2022, Efthymiadou et al.26 published a study where they examined the role of MEAs in improving the availability and timely access to a sample of cancer drugs that had received at least one reimbursement rejection. They studied funding decisions for all cancer drugs approved between 25 24 25,000 Hepatitis C patients receive new treatment. https://www.england.nhs.uk/blog/25000-hepatitis-c-patients-receive-new-treatments/ 25 Facey KM, Espin J, Kent E, Link A, Nicod E, O’Leary A, Xoxi E, van de Vijver I, Zaremba A, Benisheva T, Vagoras A, Upadhyaya S. Implement- ing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel. Pharmacoeconomics. 2021 Sep;39(9):1021-1044 26 Efthymiadou, O., Kanavos, P. Impact of Managed Entry Agreements on availability of and timely access to medicines: an ex-post evaluation of agreements implemented for oncology therapies in four countries. BMC Health Serv Res 22, 1066 (2022).

2009 and 2018 in Australia, England, Scotland, and Sweden. Of the 59 previously rejected technology- Background Paper | Documento de base indication combinations studied, 88.2% (n=45) received a favorable decision after resubmission where a MEA was proposed, versus 11.8% (n=6) where no such agreement was proposed. The average time from the original submission to the final coverage decision was 404 (±254) and 452 (±364) days for submissions without and with MEAs, respectively. New submissions that included a MEA were more likely to receive a favorable funding decision compared to those without. The time to the final funding decision was greater for those agreements based on clinical outcomes than when hard outcomes were used instead of surrogates. Barriers and Facilitators In general, MEA are more likely to be successful if they are simple, supported by robust clinical data, and easily monitored. Other factors that seem to facilitate successful implementation and effective program design include the existence of a legal framework to support patient enrollment and clear contracts with precise definitions. Adoption of MEA is further facilitated where the performance assessment of the therapy is linked to clear, measurable, realistic, and objective metrics. Culture seems to play a role in the degree of acceptance of certain types of agreements. For example, PBAs (schemes frequently adopted in the United States) are often used for innovative and expensive drugs to treat conditions with high unmet clinical need such as orphan diseases. In countries where price controls for new drugs do not apply, such as the United States, agreements based on performance or coverage with evidence development may be more feasible than financial discounts. The level of trust and willingness to negotiate between payers and pharmaceutical companies were also found to be factors that could facilitate or hinder the implementation of this type of agreement. Despite the potential advantages of MEAs, there are authors who suggest their implementation is often labor and resource intensive, which is more pertinent to clinical outcomes-based agreements or those requiring evidence development.27 28 For agreements to be implemented well, they require services that can meet their operational, administrative, and financial requirements with availability of adequate and reliable data systems capable of monitoring them. Another potential barrier reported in the literature pertains to the quality of data and evidence. The need for good quality data on prices and real-world evidence on clinical outcomes must be considered in the implementation of this type of agreement. In addition, important contextual factors were identified in the literature review as potential challenges that can hinder implementation, for instance: price transparency, confidentiality of agreements, competition regulation, and information on discounts and refunds. Other studies note the challenges related to the confidentiality of the agreements, which can inhibit the ability to analyze the trends and impacts of the MEA programs and using this knowledge to inform future decisions. 3.5 POSSIBLE FUTURE USES In Garrison et al work they identified and mention good practices and recommendations for the implementation of managed entry agreements and risk sharing agreements.29 27 Ferrario, A. et al. (2017), “The Implementation of Managed Entry Agreements in Central and Eastern Europe: Findings and Implications”, Pharma- 26 coEconomics, Vol. 35/12, pp. 1271-1285. 28 Health Care Financing and Affordability in the Emerging Global Markets. Jakovljevic; Souliotis; Groot. Frontiers Media SA. 2016 29 Garrison, L. et al. (2013), “Performance-Based Risk-Sharing Arrangements—Good Practices for Design, Implementation, and Evaluation: Report of the ISPOR Good Practices for Performance-Based Risk-Sharing Arrangements Task Force”, Value in Health, Vol. 16/5, pp. 703-719, http://dx.doi. org/10.1016/j.jval.2013.04.011.

Background Paper | Documento de base Presented below are some of the potential uses of MEA in the region: • Expanding coverage: Expanding coverage of high-cost and innovative treatments not currently available to all patients. By sharing financial risks, payers may be more willing to cover these treatments, allowing greater access for those who need it. • Adaptation to local contexts: MEA could be adapted to the specific needs and conditions of each country or region. This would require consideration of factors such as disease prevalence, available resources, and public health priorities. By customizing agreements, a more equitable distribution of resources and fairer access to treatment could be ensured. • Multi-stakeholder engagement: In the future, MEA could increasingly involve more stakeholders, such as patient organizations, public health experts, and medical societies. This would allow for greater transparency, representation, and participation in decision-making, which could lead to more equitable and efficient agreements. • Implementation of monitoring and assessment strategies: It is crucial to have strong monitoring and assessment mechanisms to ensure the success of MEA. In the future, more robust strategies could be implemented to measure agreement outcomes, and to assess their impact on treatment access, and to make adjustments based on the lessons learned. It should be recognized that clinical outcome-based agreements are resource intensive and they make reimbursement funding mechanisms more complex and dependent on health outcomes, which can divert attention from price negotiations and the ultimate budget impact of health technology delivery. It is therefore helpful for payers to establish an overall strategy or clear policy and guidelines for determining when to use an outcomes-based agreement. Such a strategy can situate these agreements and their role within the overall coverage decision-making process and they include a defined governance framework and transparency requirements. The commitments established in the framework of a MEA, with its confidentiality clauses and the need for prospective data collection during a certain period of time, can hinder the participation of products that enter the market later, which reduces competition. For this reason, where there is data to suggest that competition from upcoming products is imminent, this should be taken into account when deciding whether an RSA is appropriate. If an agreement is pursued in such a situation, it should be designed so that the agreement commitments do not inhibit the competition value of new products. A value framework is a tool to support transparent decision making that payers can use in their decisions about whether or not to use a clinical outcomes-based agreement. Such a framework should compare the value of the incremental information about product performance generated in an MEA against the incremental cost of its negotiation and execution. One possible framework has been suggested, for example, by NICE’s Decision Support Unit. Earlier work by Hutton, Trueman, and Henshall (2007) and Garrison et al. (2013) also suggested approaches to determine when agreements based on clinical outcomes are appropriate.30 31 27 30 Hutton J, Trueman P, Henshall C. Coverage with evidence development: an examination of conceptual and policy issues. Int J Technol Assess Health Care. 2007 Fall;23(4):425-32. 31 Garrison, L. et al. (2013), “Performance-Based Risk-Sharing Arrangements—Good Practices for Design, Implementation, and Evaluation: Report of the ISPOR Good Practices for Performance-Based Risk-Sharing Arrangements Task Force”, Value in Health, Vol. 16/5, pp. 703-719, http://dx.doi. org/10.1016/j.jval.2013.04.011.

4. REGIONAL EXPERIENCES Background Paper | Documento de base Gene Therapy Access Strategy (onasemnogene abeparvovec (ZOLGENSMA®) Spinal Muscular Atrophy (SMA): Argentina Experience Natalia Soledad Messina - Directorate of Special and High-Cost Drugs, Ministry of Health, Argentina Background Spinal muscular atrophy (SMA) is an inherited neuromuscular condition that affects nerve cells (motor neurons) in an area of the spinal cord called the anterior horn. Without treatment it is a disease that leads to severe disability and death. Four subtypes have been defined based on the age of onset and the severity of the disease. The SMA Type I form is the most common and severe (58%) with symptoms appearing in children, with an estimated prevalence of approximately 1/30,000. Given this prevalence, the pathology is framed in the National Law of Rare Diseases No. 26,689. In 2019, the National Administration on Drugs, Foods, and Medical Devices (ANMAT) in Argentina approved for 1-year term the drug nusinersen under special conditions for this pathology (Spinraza®), this approval was renewed for the same term but excluding SMA type 3 from such approval. In the situation of increasing judicialization and no response from the State to patients without health coverage, in January 2021, the Ministry of Health added Spinraza®32 to the Supervised Program (Programa de Tutelaje), thus providing coverage to this group of people. They defined inclusion and exclusion criteria to access it, which must be determined by the National Commission on Spinal Muscular Atrophy known as CONAME. While Argentina was in the process of covering the drug nusinersen as described, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory agencies approved the first gene therapy to treat SMA, causing a significant impact on health systems around the globe since its launch came with a price of USD 2.1 million. Consequently, in February 2021, the ANMAT through Provision No. 484/2021 approved and granted 5-year registration to the first recombinant gene therapy onasemnogene abeparvovec (Zolgensma®) that uses a non-replicating adeno-associated virus (AAV9) to deliver a copy of the SMN1 gene that encodes the human SMN protein. Single intravenous administration of Zolgensma® results in cell transduction and expression of SMN protein in humans under another mechanism of action. In May 2018, the therapy was approved by the U.S. Food and Drug Administration (FDA) for the treatment of pediatric patients under 2 years of age with SMA, with biallelic mutations in the survival motor neuron 1 (SMN 1) gene.33 On 18 May 2020, in Europe it received conditional marketing authorization valid throughout the European Union. This became a full marketing authorization on 17 May 2022.34 From the moment prior to its approval by ANMAT, the technical teams of the National Ministry of Health began to analyze the available evidence, providing the producing laboratory with information about the published clinical trials. At the same time, a technology assessment report was jointly conducted by CONAME35 and the National Commission for the Assessment of Health Technologies (CONETEC), which was published in 32 Disposición 2/2021 incorporando nusinersen como tecnología tutelada publicada en el B.O. 28 https://www.argentina.gob.ar/normativa/nacional/disposici%C3%B3n-2-2021-346519/texto 33 FDA Zolgensma https://www.fda.gov/vaccines-blood-biologics/zolgensma acceso 25/06/2023. 34 EMA Zolgensma http://www.ema.europa.eu/medicines/human/EPAR/zolgensma acceso 25/6/2023 35 Conformación CONAME. Resolución MSAL 1860/2020 publicada en el B.O: https://www.boletinoficial.gob.ar/detalleAviso/prime- ra/237295/20201113#:~:text=RESOL%2D2020%2D1860%2DAPN%2DMS&text=CONSIDERANDO%3A,de%20ellas%20y%20sus%20familias.

Background Paper | Documento de base January 2021 and updated in August of the same year.36 This report allowed the health authority to lay the foundations to start talking about a possible RSA. It is important to point out that during this time there was a significant increase in legal proceedings for access to this treatment, even in patients who were not candidates for this technology, which created serious repercussions in the media and social networks. In 2021, there were nine injunctions initiated to obtain the gene therapy, and 12 actions were initiated in 2022. In many of these cases, the drug had to be acquired by court order at the international retail price for this drug, which for Argentina was USD 2,057,000. Towards a comprehensive access strategy: key aspects of shared risk agreements In order to address this extremely high-priced innovative technology in a comprehensive and centralized way, it was necessary to design a strategy with a new purchasing model. In this model payment becomes conditional on the therapeutic outcome; and this, in turn, can be framed within the contracting laws of Argentina. This required a succession of administrative acts which, in combination with the analysis of evidence by the technical teams of both the producing laboratory and the Ministry of Health, laid the foundations to arrive at a definition of the patient profile, criteria of inclusion and exclusion for treatment access, and the different clinical milestones expected to be reached according to age for those eligible to receive treatment. It is important to highlight that since 2020, the Directorate of Special and High-Cost Drugs has successfully developed the access strategy to the drug nusinersen (Spinraza®), with a SMA registry that currently contains 229 patients37 (Unified Supervised Registry of Technologies for patients with SMA: RUTT-AME) along with the National SMA Commission’s fundamental role to assess cases for initiation and continuity of treatment according to the information presented. This creates greater certainty regarding the potential number of patients for inclusion, age of diagnosis, place of treatment, center of reference, type of coverage, etc. Finally, although obtaining a lower price for Argentina was a fundamental issue, the primary intent was price transparency, that is, the non-confidentiality of the agreed price per vial. Such confidentiality conditions are generally required by industry as seen in international experiences with this type of agreement. After a long process, the advancement of this strategy began to occur after the National Ministry of Health received a letter of intent from the Novartis laboratory. This motivated the formal incorporation of the technology in January 202338 into the National Program for Supervised Health Technologies, and after this a process for the purchase of onasemnogene abeparvovec (Zolgensma®) was commenced. It was issued through a document that incorporated the following aspects: • An open purchase for exclusivity, which uses a reference price per vial of USD 1,300,000 + VAT with logistics to the infusion center included, scheduled for 12 treatments and for a period of 12 months over the validity of the contract. 29 36 CONETEC. informe rápido N° 1 https://www.argentina.gob.ar/sites/default/files/2021/01/informe_1-zolgensma.pdf 37 Datos relevados del RUTT-AME del día 22/6/2023 38 Disposición 2/2023 incorporando onasemnogene abeparvovec como tecnología tutelada publicada en el B.O. https://www.argentina.gob.ar/normati- va/nacional/disposici%C3%B3n-2-2023-378405

• Payment will be subject to the patient outcomes produced by the therapy, as expressed in Background Paper | Documento de base the same document and will be made through an advance of 20% with the infusion, and, as long as it reaches the variables by the age indicated in the document, the remaining balance disbursed as follows: ○ 20% at 12 months post-infusion ○ 20% at 24 months post-infusion ○ 20% at 36 months post-infusion ○ 20% at 48 months post-infusion Given the particular characteristics of gene therapy treatment, patients will have to be assessed at the time of therapy administration and for a minimum period of 6 years after this. The assessment of motor scales must be completed in a detailed manner for each component. The professionals in charge of these assessments must prove their training in said techniques in accordance with the parameters defined by CONAME. This strategy is completed through the creation of a new CONAME39, that will continue to determine if the patients added by their treating physicians in the RUTT-AME meet the inclusion criteria for the different available treatments. The CONAME will have expanded powers to assess the evolution of these patients regarding their compliance with the established milestones, and this information will be necessary to proceed with the agreed payment by the contracting parties as specified in the RSA. These criteria have been prepared by the technical teams and CONAME, based on the best available evidence and are presented in Annexes II and III of the recent Resolution 1234/2023. Both the Specifications and Particular Conditions of the purchase as well as Annex III of the recent resolution stipulate monitoring guidelines for the patient assessment that are to be followed before the payment to the laboratory can be made. These guidelines are established in the following way: If one or more of the following HINE scale (Hammersmith Infant Neurological Examination) criteria are met, this will be considered as response to treatment: • Increase ≥ 2 points in the motor milestones category of kicking ability • Achievement of the maximum score in that category (touching the toes) • Increase of 1 point in the motor milestone category of head control, rolling, sitting, crawling, standing or walking Additional response to treatment will be recognized if one or more of the following CHOP INTEND (The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) is met: improvement ≥ 4 points or stabilization of the situation since treatment initiation. In relation to effects on respiratory function, a reduction in the requirement of respiratory support will be considered as a response to treatment for patients <9 months of age. The following criteria are considered as a lack of response to treatment: • For motor milestones, worsening is defined as the loss of a previously acquired motor milestone. The loss must be confirmed with two separate assessments, separated by a period of not less than three weeks. 39 CONAME, criterios de inclusión y pautas de seguimiento. Resolución MSAL 1234/2023 publicada en el B.O. 30 https://www.boletinoficial.gob.ar/detalleAviso/primera/288590/20230621

Background Paper | Documento de base • For respiratory mechanics, worsening is considered if any of the following situations occurs (outside of an acute event): 1) requirement of invasive ventilation, 2) requirement of non- invasive ventilation in a patient who previously did not require it, 3) requirement of non- invasive ventilation for more than 6 hours a day in a patient who previously required non- invasive ventilation for less than 6 hours. Furthermore, certain milestones were determined that are expected to be reached by age, as described below: • For 12 months: 1) maintenance of baseline respiratory status and mechanics; 2) maintenance of previously acquired motor milestones. • For 18 months: 1) CHOP INTEND > 40; 2) maintenance of baseline respiratory status and mechanics; 3) maintenance of previously acquired motor milestones. • For 24 months: 1) maintenance of baseline respiratory status and mechanics; 2) maintenance of previously acquired motor milestones; 3) sit independently for at least 30 seconds or roll over. • For 36-48 months: 1) maintenance of baseline respiratory status and mechanics; 2) maintenance of previously acquired motor milestones; 3) sit independently for 30 seconds or more and roll over. To achieve this, in each instance the laboratory must submit a note to the Directorate of Special and High-Cost Drugs requesting an assessment of the patient to determine if they meet the milestones required by age and that the criteria for suspension of payment are not met. CONAME then intervenes for this purpose as their role is necessary to be able to continue with the payment to the laboratory. The process established by the Argentinian Ministry of Health for funding Zolgensma® is a «risk sharing agreement» where payment is subject to the realization of the anticipated clinical benefits, with predetermined objectives upon which the continuation (or not) of funding of the medicine will depend. Managed entry agreements: Brazil’s Approach Luciene Fontes Schluckebier Bonan – Director, CONITEC Risk Sharing Agreements (RSAs) present a way to incorporate technologies into the Brazilian public health system. However, this approach is under development and not yet fully implemented. Political interest in this topic began in 2019 with a RSA pilot project proposal for the drug nusinersen in patients with spinal muscular atrophy (SMA) types II and III. The National Committee for Technology Incorporation (Conitec) had already assessed this product months before and recommended coverage only for type I of the disease. A RSA was proposed in this case, initiated by the Ministry of Health as an access alternative for patients not included in coverage (Denizar et al., 2022). However, based on a legal evaluation of the process the pilot project could not be implemented because it was not preceded by an assessment by Conitec, which is required according to Brazilian law. From this point, the Executive Secretariat of Conitec began work to understand the theoretical and practical aspects of the RSA, which included the organization of workshops with health authorities from various countries, as well as technical visits to countries such as England, Spain, and Italy. The Ministry of Health also began experimenting with other forms of managed access agreements based on volume discounts, rebates after reaching a limit on the number of treatments, as well as conditional requirements to reassess after 3 years of monitoring technology effectiveness. In 2021, due to the interest expressed by a pharmaceutical company to build an agreement prior to the submission of the reimbursement dossier to Conitec, a case study was carried out for an RSA 31

proposal for Zolgensma® in the Brazilian context. The case study was developed over five meetings Background Paper | Documento de base between August and December 2021. The result of this exercise would not necessarily be used as a proposal for coverage by the company nor be tied to a health system decision about reimbursement. During these meetings, innovative access models in Latin America presented by the Latin American Federation of the Pharmaceutical Industry (FIFARMA) were discussed. Additionally, the challenges and alternatives present in the new Brazilian legislation on public procurement and contracts were explored, as this would permit the legal use of alternative contracting models for product procurement by public entities in Brazil. The pharmaceutical industry also presented possibilities of payment models for Zolgensma®, with consideration to different formats and implementation complexities based on ongoing experiences in other countries. In the development of the case study, the Conitec Executive Secretariat constructed an example RSA for the therapy. The RSA was a performance-based agreement indicated only for patients up to the age of six months with SMA type I of the 5q gene, with deferred payment installments. This proposal considered the studies of Zolgensma® published to that point along with the uncertainties related to long-term therapy performance. Since this was an exploratory exercise, it included a highly complex model to anticipate and discuss all the negotiation and implementation challenges that a RSA might encounter in a real situation. At the time, the therapy did not have a defined price for commercialization in Brazil and, according to the company, the decision to actually propose an agreement would depend on the price determined by the Brazilian Medicines Market Regulation Chamber (CMED). In 2022, with the price of the therapy set at a much lower level than expected by the company (R$ 6.5 million compared to R$ 12 million), the coverage proposal presented to Conitec included a proposal for a RSA but with a much more modest design. The price proposed for reimbursement was R$ 5.7 million and the intended target population was children up to two years of age. Payment would be made in three installments (50% at the time of infusion; 30% after 12 months; and, 20% after 24 months), provided only in the absence of mortality or the need for permanent invasive ventilation due to disease progression. The Conitec Plenary assessed the proposal presented by the company and considered it insufficient. During public consultation, which is done for all technology reimbursement processes in the single healthcare system (SUS), the company presented a new proposal. This revised proposal included payment in five equal installments (20%) over 5 years and the inclusion of maintenance outcomes or motor improvement milestones, assessed by means of a score on a specific scale (CHOP-INTEND) along with a limit on annual treatments above which point treatments would be provided free of charge to the Ministry of Health. Ultimately, Conitec recommended coverage of Zolgensma® for patients up to 6 months of age with type I SMA who are off invasive mechanical ventilation for more than 16 hours a day in accordance with the RSA. The first coverage decision in Brazil with an explicit provision for an RSA was published in December 2022. In the same month, a publication was released about the new organization of technology reimbursement processes in the SUS. This new regulation included provisions for conditional coverage and managed access to reimbursed technologies. It also created a Technical Subcommittee on Managed Access within Conitec, which has powers related to monitoring and reassessment of reimbursed technologies, as well as the definition of guidelines, criteria, methods, and workflows for the execution of MEAs and their implementation in the SUS. Through this experience some challenges and lessons learned can be identified. First, similar to the institutionalization of HTA in Brazil, the use of RSAs as a mechanism for technology reimbursement depends on certain prerequisites. The first of these refers to awareness of and commitment to the subject, both at a political and a technical-bureaucratic level, since RSAs require a significant transformation in the organizational culture. The implementation of the agreements entails an 32

Background Paper | Documento de base intense administrative burden, with corresponding changes in workflows and work processes. Second, there is the need for an explicit regulatory framework specific for RSAs, with a simultaneous strengthening of HTA, so as to avoid parallel reimbursement pathways. In Brazil, the health system arrangement is complex, with both the centralized procurement of technologies by the Ministry of Health, as well as the possibility of purchase and funding by federal entities (states and municipalities) and the private supplementary health insurance sector. In addition, health system priorities need to be clearly defined to be able to identify situations where the interests of manufacturers, individuals, and payers are aligned. In this context, the key lies in the proximity and mutual recognition among these stakeholders, which makes it easier to find appropriate solutions to the various challenges that may arise along the way. References: Denizar Vianna, Camile Giaretta Sachetti, Patrícia Boaventura. Acordo de Compartilhamento de Risco: projeto-piloto no Sistema Único de Saúde. J Bras Econ Saúde 2022; 14 (supl 1): 101-7). DOI: 10.21115/JBES.v14.n1.(Supl.1):101-7. Managed entry agreements: Experience of Uruguay Graciela Fernandez - Technical-Medical Deputy Director of Evaluation of FNR Management The National Resources Fund (FNR) in Uruguay is a non-state public body that, since 1981, has administered universal insurance coverage for harms caused by high healthcare costs, covering high-cost diagnostic and therapeutic procedures and high-priced medicines. This insurance has as beneficiaries all people living in the country. The Ministry of Health has the responsibility to select technologies that have coverage guaranteed by the National Integrated Health System, including those that are covered by the FNR. The technologies that have coverage guaranteed by the National Integrated Health System are all included in either the Comprehensive Health Care Plan (PIAS) (for diagnostic and therapeutic procedures and techniques), or in the Therapeutic Formular of Medicines (FTM) (for drugs). Once a technology is covered by the FNR, it becomes the responsibility of the FNR regarding price negotiation of medicines, as well as the identification of commercial brands and indications for coverage. Specifically with regard to drugs, the FNR is empowered with certain advantages when negotiating with industry: • The FNR is the only buyer of high-priced medicines in the country, with payment ensured within 60 days of receiving the invoice. • Due to its non-state legal form, it is governed by private law when negotiating prices with industry, and it maintains transparency and participation of the management team and representatives of the Administrative Honorary Commission in purchasing decisions. • Most purchase agreements are made in Uruguayan pesos without clauses or adjustment parameters. Some signed agreements have been implemented for a two year term. • Purchases are made through the PAHO Strategic Fund and jointly with MERCOSUR and UNASUR countries. • Different negotiation models are used with the industry. Risk sharing agreements have been made with some manufacturers. 33

Different agreement formats have been implanted at different times: Background Paper | Documento de base • Total volume: the higher the volume, the lower the price. • Units consumed-outcomes: here payment is made based on units consumed, for example only up to the expected survival rate. If patients live longer than the expected survival rate, the drug is provided free of charge by the manufacturer. • Adherence (average dose): bonuses for patients with good adherence assessed at one year. The FNR pays for the medication according to consumption, but only up to the expected monthly average of adherence; if patients consume a product amount greater than this average, the manufacturer provides the drug free of charge. • Fixed monthly payment: Flat rate: ○ Adjusting the price for a group of drugs for the same pathology, e.g., breast cancer if the minimum quota of patients is not met or if the maximum is exceeded. There is increased coverage but with the same expense. ○ For a group of drugs for several different treatments, e.g., rheumatoid arthritis, lymphomas, and chronic lymphoid leukemia there is a global price reduction of 8%. A recent example: Treatment of hemophilia A in the pediatric population with Emicizumab without inhibitors Emicizumab entered the FTM under the remit of the FNR by Ministerial Order 1938/2021 according to coverage criteria that includes patients aged ≥1 year with Factor VIII inhibitors and patients aged ≥12 and <18 without Factor VIII inhibitors VIII. A special outcomes-based program was implemented for pediatric patients from 1 to 11 years of age inclusive with hemophilia “A” without inhibitors who were not eligible for coverage (03/04/2022). These patients must meet the same inclusion requirements as stated in the coverage regulations for patients of the same age group with inhibitors. The program was one-year in duration and the implementation site was the main pediatric hospital in the country. This site was chosen given the high number of patients with this pathology that are managed there and the attending professionals with relevant expertise. It was agreed that the manufacturer would provide a set number of milligrams of the drug (50,000) free of charge to be used exclusively in these patients during the duration of the program. After one year of the program, an assessment was conducted by the FNR. This group of patients would receive coverage as long as at least one of the following conditions was met: • At least 85% of the patients do not present spontaneous bleeding that requires additional actions for resolution. • The annualized rate of spontaneous bleeding is less than 1 bleed/patient/year. The operational definitions used were as follows: • Any bleeding appearing in the same topography up to 72 hours after treatment is considered as the same bleeding. • Any bleeding in a different topography will be considered a new bleeding regardless of the treatment time. 34

Background Paper | Documento de base • Bleeding will be recorded from the second month of treatment (full load) and patients with at least 6 months of treatment who have received all the corresponding doses will be considered. The FNR aims to send the collected and anonymized data every 4 months. In accordance with the agreement, in December 2022 the scheduled assessment was carried out, which showed that of the 26 patients included in the program there were no cases of spontaneous bleeding that required the additional actions for resolution. In conclusion, and in accordance with the agreement, the FNR Honorary Administrative Commission approved the coverage of Emicizumab for patients with the characteristics defined in the program. Currently, the necessary administrative processes are being implemented to make this resolution effective (i.e., inclusion in the FTM). Some structural elements of the FNR that facilitate this type of agreement: • Political and economic stability of the country • National epidemiological information • FNR information system with complete and validated records • Coverage regulations establishing explicit criteria for inclusion, exclusion, and suspension of coverage • Availability of control instruments • Statistical data and assessment of outcomes • Budget impacts – stochastic simulation software In summary, models of different negotiation with industry have enabled efficient medicines procurement, as well as improved access and reduced risks and uncertainty. Furthermore, they allow the possibility of more realistic spending estimates with reduced uncertainty about the budget impact while providing transparency in decision-making. These models are particularly important when they are based on real-world data and, most importantly, where there is a country-wide scope and support from a powerful information system that integrates clinical data about authorizations with monitoring and administrative data. Resources and control mechanisms are required to strictly monitor the evolution of the agreements, which contribute, in some cases, to improving the quality of care through personalized monitoring of patients. References Fondo Nacional de Recursos (2021): “Tratamiento de la Hemofilia A con Emicizumab. Normativa de cobertura”. Recuperado de: https:// www.fnr.gub.uy - Normativas 35

HTAI 2023 FORO DE POLÍTICAS EN Background Paper | Documento de base EVALUACIÓN DE TECNOLOGÍAS SANITARIAS EN LATINOAMÉRICA DOCUMENTO DE ANTECEDENTES ¿Cómo los nuevos esquemas de acceso, incluyendo los acuerdos de riesgo compartido, pueden contribuir a las decisiones de cobertura? VIII Foro de Políticas en Evaluación de Tecnologías Sanitarias en Latinoamérica (Latam Policy Forum). Chile, agosto 2023. Este documento ha sido elaborado por: Sebastián García Martí, Andrea Alcaraz, Lucas Perelli, Federico Augustovski y Andrés Pichon Riviere Instituto Efectividad Clínica y Sanitaria (IECS) - Argentina Agradecemos a Manuel Espinoza, Presidente del Latin American Policy Forum 2023 de HTAi y a los integrantes del Comité Organizador: William Dorling (Pfizer), Felipe Vera (Ministerio de Salud, Chile), Luciene Bonan (Ministerio de Salud, Brasil), Adriana Maria Robayo (Instituto de Evaluación Tecnológica en Salud, Colombia), Graciela Fernandez (Fondo Nacional de Recursos, Uruguay), Fernanda Laranjeira (Medtronic), Diego Guarín (MSD), Alicia Granados (Sano- fi) por sus comentarios y sugerencias en la realización de este documento. 36

Background Paper | Documento de base MARCO GENERAL DEL POLICY FORUM 2023 Los esquemas de acceso a tecnologías (EAT), engloban distintos tipos de acuerdos entre las partes interesadas, como fabricantes de medicamentos, financiadores y pacientes, para compartir los riesgos y los beneficios asociados con la incorporación de un tratamiento en particular, son una herramienta cada vez más utilizada para abordar los desafíos en el acceso a medicamentos innovadores y de alto costo. La terminología en el idioma español puede en ocasiones tener distintas acepciones existiendo también el término acuerdos de riesgo compartido (ARC) que puede utilizarse en forma indistinta. Se explorará la posible utilidad de los mismos en América Latina, en el contexto de los desafíos en el acceso a medicamentos, la sostenibilidad financiera de los sistemas de salud y la necesidad de garantizar el acceso a tratamientos innovadores y de alta calidad. Se describirá cómo funcionan y se presentarán algunos ejemplos de implementación en la región y en el mundo. El objetivo de este documento es aportar información a los tomadores de decisiones, los responsables de políticas y los productores de tecnologías que pueda servir como insumo para promover una mejor participación de los participantes en el Foro de Políticas de Salud 2023 a realizarse en Chile. Descripción general del Documento Base 1. Sección Introducción 2. Sección Antecedentes 3. Sección Esquemas Acceso a Tecnologías a. Definición y Taxonomía b. Diferencias entre acuerdos financieros y basados en el desempeño c. Descripción de su uso en los últimos años 4. Evaluación de su utilidad potencial 5. Posibilidades de uso futuro 6. Sección Experiencias Internacionales y Regionales 7. Sección Referencias 37

1. INTRODUCCIÓN Background Paper | Documento de base Los financiadores y los productores de tecnologías, tienen como objetivo promover el rápido acceso a las mismas después de la autorización de su comercialización. Sin embargo, en ocasiones existe incertidumbre acerca del verdadero beneficio de la tecnología o del impacto presupuestario que incorporar la misma signifique para los sistemas de salud. Como una estrategia para abordar estas situaciones de incertidumbre pueden utilizarse los Esquemas de Acceso a Tecnologías (EAT), también conocidos como acuerdos de riesgo compartido, que permiten a los productores y financiadores generar acuerdos que permitan compartir el riesgo de esta incertidumbre (tanto en sus beneficios clínicos como en el impacto presupuestario) para promover la incorporación de la tecnología1. Estos acuerdos ayudan a mitigar las consecuencias de tomar decisiones de cobertura cuando existe incertidumbre sobre los efectos de un nuevo tratamiento. Tomar decisiones inadecuadas puede llevar a resultados de salud deficientes, desperdicio de recursos y disminuir la credibilidad de los procesos de toma de decisiones. Estos mecanismos se emplean para establecer modalidades de pago y condiciones de reembolso que sean justos y equitativos tanto para los financiadores y proveedores de atención médica como para los productores de tecnologías, al tiempo que se garantiza el acceso a una atención de calidad. Habitualmente estos tipos de esquemas se utilizan con mayor frecuencia en aquellas tecnologías para las cuales el impacto presupuestario de su incorporación puede ser elevado y se quiere disminuir la incertidumbre de su adopción, ya sea presupuestaria o en el desempeño clínico de las mismas. En general este tipo de acuerdos intentan “compartir” los riesgos de la incorporación de tecnologías entre el financiador y el productor en aquellas situaciones en que por características de la patología, la calidad de la evidencia o el impacto presupuestario de su incorporación la incertidumbre de su adopción sea elevada. En otras palabras, son una estrategia utilizada para compartir el riesgo entre los productores de medicamentos, dispositivos o test diagnósticos y los pagadores, ya sean sistemas de salud, proveedores de seguridad social o aseguradores privados. Estos acuerdos se establecen para garantizar el acceso a los tecnologías innovadoras y reducir el costo del tratamiento, fundamentalmente en aquellos casos donde no existe suficiente certeza acerca de si la tecnología va a tener resultados positivos en la vida real similar a la de los estudios clínicos, o porque existe incertidumbre en el resultado de los mismos. El objetivo del octavo Foro de Políticas en Evaluación de Tecnología Sanitaria en Latinoamérica de 2023 será discutir y entender la utilidad y potencial de la utilización de los Esquemas de Acceso de Tecnologías (EAT) incluyendo los Acuerdos de Riesgo Compartido (ARC) en los procesos de incorporación de tecnologías y toma de decisiones, analizar sus características, barreras y facilitadores que los diferentes actores enfrentan respecto a su utilización, y definir una serie de principios clave y acciones que puedan servir para guiar su implementación de elegir su utilización. 1 Garrison, L. et al. (2013), “Performance-Based Risk-Sharing Arrangements—Good Practices for Design, Implementation, and Evaluation: Report of the ISPOR Good Practices for Performance-Based Risk-Sharing Arrangements Task Force”, Value in Health, Vol. 16/5, pp. 703-719, http:// dx.doi.org/10.1016/j.jval.2013.04.011. 38

Background Paper | Documento de base ¿Qué es la Evaluación de Tecnologías Sanitarias (ETESA)? La ETESA es un proceso multidisciplinario que utiliza metodologías explícitas para determinar el valor de una tecnología sanitaria a lo largo de su ciclo de vida2. Su propósito es informar el proceso de toma de decisión para promover sistemas de salud equitativos, eficientes y de alta calidad. Esta información es utilizada por los sistemas de salud para tomar decisiones que afectan sobre todo la forma en que se asignan los recursos sanitarios, como por ejemplo la decisión de dar cobertura a una determinada tecnología sanitaria, o la decisión de incorporarla a un paquete de beneficios. Las tecnologías sanitarias constituyen hoy una parte indispensable de todo sistema de salud y su uso se ha incrementado en las últimas décadas. La introducción de nuevas tecnologías ha representado en general beneficios significativos, en términos de prevención, seguridad, mejoras en la salud y calidad de vida o reducción de efectos adversos. Sin embargo, en un contexto en el cual los recursos son limitados, la correcta incorporación y difusión de las tecnologías se ha convertido en un desafío y, en algunos casos, un serio problema. La rápida aparición de tecnologías y el aumento del volumen de la evidencia disponible son hoy una realidad para todos los sistemas de salud. Brindar servicios de salud implica tomar decisiones acerca de qué intervenciones deben ser ofrecidas (e implícita o explícitamente cuáles no), la forma en que se organizará el sistema de salud, quién pagará por estas intervenciones; y también cómo y quiénes deben proveerlas. El desafío es lograr resultados en salud adecuados con los recursos disponibles, habiendo contemplado también los valores sociales, las expectativas y demandas de la población. Actualmente, una gran cantidad de países se han comprometido a alcanzar la cobertura universal en salud (CUS) para su población, siendo uno de los objetivos priorizados por la Organización Mundial de la Salud (OMS). En el contexto de la CUS, la priorización de intervenciones es una estrategia central, y en los documentos desarrollados por este organismo se considera de fundamental importancia que la misma se realice en base a la mejor evidencia disponible y a través de un proceso deliberativo que tome en cuenta los valores sociales3 4. En este contexto, los decisores sanitarios han comenzado a necesitar cada vez más información confiable y detallada que les permita tomar decisiones transparentes y legítimas a la hora de fijar prioridades, para lograr obtener el máximo beneficio con presupuestos limitados. El crecimiento y desarrollo de la ETESA refleja esta demanda de información sólida y transparente que sirva como aval para tomar decisionessobre el desarrollo, incorporación y difusión de tecnologías sanitarias5. Precisamente la ETESA tiene sus orígenes en esta creciente preocupación por la expansión de nuevas y costosas tecnologías sanitarias en los 1970s y las limitaciones de los sistemas de salud para financiar su uso. Como disciplina evolucionó desde los años 70’ para convertirse en una especialidad multidisciplinaria cuyo propósito es unir y sintetizar la evidencia disponible con el fin de ayudar a los decisores sanitarios, profesionales de la salud y pacientes a entender el valor relativo de las tecnologías. 2 O'Rourke B, Oortwijn W, Schuller T; International Joint Task Group. The new definition of health technology assessment: A milestone in international collaboration. Int J Technol Assess Health Care. 2020 Jun;36(3):187-190. 3 Terwindt F, Rajan D, Soucat A. Priority-setting for national health policies, strategies and plans. In: Schmets G, Rajan D, Kadandale S, eds. Strategizing national health in the 21st century: a handbook: World Health Organization (WHO); 2015:71 4 World Health Organization (WHO). Making fair choices on the path to universal health coverage. Final report of the WHO Consultative Group on Equity and Universal Health Coverage 2014: http://apps.who.int/iris/bitstream/10665/112671/1/9789241507158_eng.pdf?ua=1. Accessed 11- 3-2016 5 Gabbay J, Walley T. Introducing new health interventions. BMJ. 2006;332(7533):64-65. 39

El desarrollo de la ETESA ha sido especialmente notable en los últimos 20 años y constituye hoy un Background Paper | Documento de base componente indispensable de los sistemas de salud de muchos países. En la región de Latinoamérica y el Caribe (LA) han surgido varias iniciativas. Argentina, Brasil, Colombia, Chile, México y Uruguay cuentan con agencias de ETESA miembros de INAHTA (sigla de la Red Internacional de Agencias de ETESA), y diversos países latinoamericanos aplican actualmente, en diferente medida, la ETESA en la toma de decisiones sobre asignación de recursos. La mayor parte de estas iniciativas de la región están agrupadas en RedETSA, la red de evaluación de tecnologías sanitarias de América Latina (http://redetsa.org/), coordinada por la Organización Panamericana de la Salud (OPS). La ETESA tiene la potencialidad de ser una herramienta de gran utilidad para los tomadores de decisión. Sin embargo, si no se realiza y utiliza de forma adecuada, se corre el riesgo de producir una asignación ineficiente de recursos, dar cobertura a intervenciones de poco o nulo beneficio, impedir o demorar el acceso de pacientes a tecnologías sanitarias útiles, exponer a los pacientes a riesgos innecesarios, y enviar mensajes equivocados a los productores de tecnologías, entre otros6. A su vez, la ETESA no es un ejercicio puramente técnico, y el proceso de toma de decisiones debe tomar en cuenta dimensiones cada vez más amplias. Por estos motivos, dado que las decisiones que se tomarán a través del proceso de ETESA tienen el potencial de afectar a un gran número de personas e instituciones, se han propuesto una serie de principios básicos que la ETESA debería cumplir. Estos principios incluyen aspectos como la transparencia en el procesos de realización de ETESA y la toma de decisión, el involucramiento de actores relevantes, la existencia de mecanismos explícitos para decidir qué tecnologías serán evaluadas, y la existencia de un vínculo claro entre la evaluación y la toma de decisión.7 8 9Muchos de estos aspectos fueron tratados en las diferentes ediciones del Foro de Políticas de HTAi para Latinoamérica.10 11 12 13 14 15 6 Wilsdon T, Serota A. A comparative analysis of the role and impact of health technology assessment. London:UK: Charles River Associates; 40 2011.http://www.phrma.org/sites/default/files/pdf/hta_final_comparison_report_13_may_2011_stc1.pdf 7 Daniels N, Sabin J. Setting limits fairly: learning to share resources for health. 2nd ed. New York: Oxford University Press; 2008 8 Drummond MF, Schwartz JS, Jönsson B, Luce BR, Neumann PJ, Siebert U, Sullivan SD. Key principles for the improved conduct of health tech- nology assessments for resource allocation decisions. Int J Technol Assess Health Care. 2008. Summer;24(3):244-58; discussion 362-8 9 Pichon-Riviere A, Augustovski F, Rubinstein A, Martí SG, Sullivan SD, Drummond MF. Health technology assessment for resource allocation decisions: Are key principles relevant for Latin America? Int J Technol Assess Health Care. 2010 Oct;26(4):421-7 10 Pichon-Riviere A, Soto NC, Augustovski FA, García Martí S, Sampietro-Colom L. Health techonolgy assessment for decision making in Latin America: good practice principles. Int J Technol Assess Health Care, 34:3 (2018), 1-7 11 Pichon-Riviere A, Soto NC, Augustovski FA, Sampietro-Colom L. Stakeholder involvement in health technology assessment process in Latin America. Int J Technol Assess Health Care, 34:3 (2018), 1 13 Pichon-Riviere A, GarciaMarti S, Oortwijn W, Augustovski F, SampietroColom L (2019). Defining the Value of Health Technologies in Latin America: Developments in Value Frameworks to Inform the Allocation of Healthcare Resources. International Journal of Technology Assess- ment in Health Care 35, 64–68 12 Pichon-Riviere A, GarciaMarti S, Oortwijn W, Augustovski F, SampietroColom L (2019). Defining the Value of Health Technologies in Latin America: Developments in Value Frameworks to Inform the Allocation of Healthcare Resources. International Journal of Technology Assessment in Health Care 35, 64–68 13 Pichon-Riviere A, Augustovski F, García Martí S, Alfie V, Sampietro-Colom L (2020). The link between health technology assessment and decision making for the allocation of health resources in Latin America. International Journal of Technology Assessment in Health Care 36, 173–178 14 Pichon-Riviere A, Augustovski F, García Martí S, Alcaraz A, Alfie V, Sampietro-Colom L (2021). Identification and selection of health technologies for assessment by agencies in support of reimbursement decisions in Latin America. International Journal of Technology Assessment in Health Care 1–8 15 Alcaraz A, Pichon-Riviere A, García-Martí S, Alfie V, Augustovski F, Castro H. Deliberative processes in decision making informed by health technology assessment in Latin America. Int J Technol Assess Health Care. 2022 Dec 16;38(1):e86.

Background Paper | Documento de base 2. ANTECEDENTES Y OBJETIVOS DEL FORO El Foro de Políticas de Evaluación de Tecnologías Sanitarias (del inglés Policy Forum) es una actividad organizada por HTAi (de su sigle en inglés Health Technology Assessment International). Se creó en el año 2004 con el objetivo de proporcionar un espacio neutral para llevar a cabo discusiones de carácter estratégico sobre el estado presente de la ETESA, su desarrollo, y sus implicancias para los sistemas de salud, la industria, los pacientes y otras partes interesadas. El mismo convoca a representantes de tres grupos principales de instituciones: 1) tomadores de decisión sobre la cobertura y reembolso/precios de medicamentos y dispositivos en los sistemas de salud; 2) organismos que realizan ETESA en apoyo de estas decisiones; y 3) empresas biomédicas productoras de tecnologías. Se realiza desde hace 17 años con foco en Europa y EE.UU; y desde hace 10 años, en Asia. En el año 2016 comenzó a realizarse también en Latinoamérica, siendo este el octavo Foro que se realizará en la región. El enfoque, la agenda y los detalles logísticos fueron desarrollados por un Comité Organizador compuesto por el presidente del Foro y representantes de las instituciones participantes (tres representantes del ámbito público y tres representantes del ámbito de empresas productoras de tecnología). El Instituto de Efectividad Clínica y Sanitaria de Argentina (IECS – www.iecs.org.ar) actuó como la Secretaría Científica. El proceso de selección del tópico de este octavo Foro comenzó durante el séptimo Foro e incluyó los siguientes pasos: 1. Se procedió a la elaboración de un listado de temas potencialmente relevantes a partir de las propuestas/temas sugeridos por parte de los miembros del Foro Latinoamericano y se realizó una votación durante el cierre del Foro 2022 para identificar los tópicos más prioritarios para el 2023. 2. Envío de dicho listado a los miembros del Comité Organizador para sus comentarios/ sugerencias. 3. Selección del tópico final a través de un proceso deliberativo en el Comité Organizador En base a este proceso, el tópico seleccionado para este séptimo foro fue “Cómo los nuevos Esquemas de Acceso a Tecnologías, incluyendo los Acuerdos de Riesgo Compartido, pueden contribuir en las decisiones de cobertura”. Esta octava edición del Policy Forum Latinoamericano se concatena con los siete anteriores: Policy Forum 2016: El primero de los Policy Forum de LA se realizó en Costa Rica. En este encuentro se discutió sobre los “Principios de buenas prácticas en la aplicación de la Evaluación de Tecnología Sanitaria en la toma de decisiones en Latinoamérica”. Como resultado del mismo los principios priorizados como más relevantes para promover la aplicación de ETESA en LA fueron: • Transparencia en procesos de realización de ETESA y de comunicación de sus resultados • Involucramiento de los actores relevantes en el proceso de ETESA • Existencia de mecanismos de apelación • Existencia de mecanismos claros para el establecimiento de prioridades en ETESA • Existencia de un vínculo claro entre la evaluación y la toma de decisión Policy Forum 2017: Este segundo Policy Forum, llevado a cabo en Lima, tuvo como tema central la incorporación de distintos actores en el proceso de Evaluación de Tecnologías Sanitarias, un aspecto que había sido identificado como prioritario durante el primer Policy Forum. Policy Forum 2018: Se realizó en Montevideo en 2018 y discutió sobre marcos de valor en ETESA. 41

Policy Forum 2019: Se realizó en Buenos Aires y tuvo como eje la relación entre la ETESA y la toma de Background Paper | Documento de base decisiones. Policy Forum 2020: Fue realizado en forma on-line y discutió los mecanismos utilizados por las agencias de ETESA para priorizar las evaluaciones a realizar. Policy Forum 2021: También realizado en forma on-line, discutió el rol de los procesos deliberativos en la ETESA Policy Forum 2022: Se realizó en Brasilia y tuvo como objetivo conversar sobre la utilización de Evidencia de Vida Real en los procesos de ETESA (Todos los resultados de las discusiones mantenidas durante estos cinco Policy Forum están disponibles en una serie de publicaciones: Pichon-Riviere et al 2018-2022) Los objetivos principales de este octavo Foro de Políticas en Evaluación de Tecnología Sanitaria en Latinoamérica serán: Explorar el estado actual de la utilización de EAT/ARC en los procesos de ETESA en Latinoamérica Explorar las utilidades/limitaciones/barreras/riesgos y las oportunidades para la implementación de AET/ARC en la Región Discutir e identificar los principales aspectos contextuales que deberían tenerse en cuenta en la región al momento de implementar EAT/ARC, así como principios de buenas prácticas para llevarlos adelante Discutir la potencial aplicabilidad de diferentes modelos utilizados en el mundo a los sistemas de salud de Latino América, y generar una serie de recomendaciones para guiar la implementación de EAT/ARC en la incorporación de ETESA en América Latina. El objetivo de este documento base es proveer información que sirva de punto de partida para las discusiones que se desarrollarán en el foro de políticas HTAi de Latinoamérica 2023 que se llevará a cabo en forma presencial los días 14 y 15 de agosto, en la ciudad de Santiago, Chile. La información proviene de una búsqueda bibliográfica enfocada en EAT/ARC y ETESA y de la revisión de los sitios web de agencias y sistemas de salud. 3. SECCIÓN ESQUEMAS DE ACCESO A TECNOLOGÍAS SANITARIAS a. Definición y Taxonomía Existen distintas modalidades de EAT y no hay una clasificación estándar que englobe todos los 42 tipos de acuerdos. Sin embargo, se pueden identificar dos categorías principales: acuerdos basados en resultados financieros y acuerdos basados en resultados en salud16. Ambos tipos tienen el objetivo de compartir los riesgos entre el financiador y el proveedor asociados a la incorporación de tecnologías cuando existe incertidumbre. Sin embargo, abordan diferentes tipos de incertidumbres. 16 Carlson, J. et al. (2010), “Linking payment to health outcomes: A taxonomy and examination of Health Policy, Vol. 96/3, pp. 179-190, http:// dx.doi.org/10.1016/j.healthpol.2010.02.005.

Background Paper | Documento de base Los acuerdos financieros se centran en reducir la incertidumbre relacionada con el impacto presupuestario de adquirir nuevas tecnologías sanitarias, mientras que los acuerdos basados en resultados en salud buscan reducir la incertidumbre en cuanto a la efectividad y relación coste- efectividad de estas innovaciones.17 Los acuerdos basados en resultados financieros (AF) tienen como objetivo gestionar la incertidumbre en torno al impacto presupuestario de una nueva tecnología. Los acuerdos financieros no están vinculados a resultados clínicos y no requieren el análisis de datos relacionados a resultados de salud. Son acuerdos contractuales que pueden establecer el precio, descuentos o niveles de reembolso y otros términos y condiciones asociados con la adquisición y/o utilización de una tecnología sanitaria. Los acuerdos basados en resultados clínicos (ABRC) constituyen un acuerdo entre un pagador y un productor que establece precios, descuentos o niveles de reembolso para un producto en función del logro de objetivos predefinidos sobre resultados clínicos. Requieren el análisis y seguimiento de resultados clínicos en aquellos pacientes involucrados en el acuerdo. Tienen también un objetivo financiero, pero este está relacionado a resultados clínicos específicamente. Se pueden observar en la Tabla 1 los distintos tipos de acuerdo agrupados en relación a su taxonomía. Tabla 1 ACUERDOS BASADOS EN ASPECTOS FINANCIEROS Descuentos Acuerdos de precio/volumen Acuerdos de límite presupuestario (Budget Capping) - Suscripción Acuerdos por límite de utilización (Utilization Capping) Acuerdos por suscripción ACUERDOS BASADOS EN RESULTADOS CLÍNICOS Acuerdos de reembolso vinculados al desempeño clínico de la tecnología Acuerdos de cobertura con generación de evidencia Acuerdos financieros A continuación, se describen cuatro tipos de acuerdos financieros comúnmente utilizados: Descuentos: Es el tipo de acuerdo más simple y habitual, implica proporcionar un descuento en el precio del medicamento o tecnología sanitaria en función de diferentes factores. Por ejemplo, puede haber un descuento por volumen de compra o por la duración del contrato. Este tipo de acuerdo es beneficioso para ambas partes, ya que el comprador obtiene el producto a un precio más bajo y el proveedor asegura un volumen de ventas. Cabe destacar que este tipo de acuerdo no corresponde a 43 17 Wenzl, M. and S. Chapman (2019), \"Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward\", OECD Health Working Papers, No. 115, OECD Publishing, Paris, https://doi. org/10.1787/6e5e4c0f-en.

lo que genéricamente se denomina riesgo compartido. Si bien podría argumentarse que un Background Paper | Documento de base descuento podría ser equivalente a una porción de riesgo asumido por el productor, debido a que esta se hace en términos de certeza, no constituye una distribución de riesgo en sí misma. La redistribución de riesgos opera sobre un precio exógeno donde previamente operó un descuento. Acuerdos de precio/volumen: Este tipo de acuerdo se basa en establecer diferentes precios para el medicamento o producto sanitario en función del volumen de ventas. Por ejemplo, el precio por unidad puede ser menor si se venden más de cierto número de unidades. Este acuerdo es beneficioso para el proveedor, ya que tiene un incentivo para aumentar las ventas del producto, y para el comprador, ya que puede obtener un precio más bajo si se alcanzan ciertos niveles de venta. Acuerdos por límite presupuestario (Budget capping): Este tipo de acuerdo se refiere a un límite de gasto preestablecido para un determinado medicamento o producto sanitario. El objetivo de este acuerdo es garantizar que el presupuesto asignado a una tecnología no supere un determinado nivel, lo que puede ayudar a controlar los costos del sistema sanitario. En ocasiones este tipo de acuerdos también suele llamarse modelos por suscripción (modelo Netflix), dado que el productor provee la cantidad de tratamientos que se requieran por un monto fijo de dinero. Acuerdos por límite de utilización (Utilization capping): Este tipo de acuerdo implica establecer un límite en el número de pacientes o dosis por paciente que pueden recibir un medicamento o tecnología sanitaria. El objetivo de este tipo de acuerdo es controlar el uso de la tecnología para asegurarse de que se utilice solo en pacientes que se beneficien de él y que estén dentro de su indicación aprobada. En resumen, los acuerdos financieros son herramientas útiles para controlar los costos y promover el acceso a las tecnologías sanitarias. Los cuatro tipos de acuerdos financieros descritos anteriormente se utilizan comúnmente en la práctica clínica para controlar el gasto, y son relativamente mucho más sencillos de implementar en relación a los basados en resultados clínicos. Acuerdos de riesgo basados en resultados clínicos 44 Se puede clasificar los acuerdos de riesgo compartido en: A. Acuerdos de reembolso vinculados al desempeño: en estos acuerdos, el reembolso del medicamento o tecnología está vinculado a su efectividad en el mundo real, lo que significa que se establecen ciertos criterios de éxito que deben cumplirse para que se produzca el reembolso completo o parcial. El objetivo es evaluar el valor real de la tecnología en un entorno de atención médica efectiva. Este tipo de acuerdo puede ser beneficioso tanto para el pagador como para el fabricante, ya que el pagador sólo paga por los medicamentos que funcionan, mientras que el productor recibe una mayor certeza financiera. Hay diferentes variantes de los mismos. Pueden estar basados en el proceso de cuidado, estando el pago relacionado con el proceso de atención, por lo que el reembolso se especifica de antemano para depender del proceso de toma de decisiones clínicas, por ejemplo, el cumplimiento de las directrices clínicas por parte de un proveedor o la selección de pacientes individuales sobre la base de un biomarcador, como una prueba genética. En otras ocasiones se generan acuerdos basados en outcomes o desenlaces en los que el reembolso se produce a posteriori, midiendo puntos finales intermedios o clínicos. Estos resultados pueden incluir medidas de eficacia, seguridad y/o costo-efectividad. Se genera una \"garantía de resultados\", por ejemplo, el fabricante puede comprometerse a proporcionar un reembolso parcial o total si el medicamento o tecnología no funciona como se esperaba. En otras ocasiones se negocia la \"continuación condicionada del tratamiento\", es decir, el pago por el uso continuado del medicamento se realiza en función de los resultados que van obteniendo los pacientes.

Background Paper | Documento de base En cuanto al relevamiento de puntos finales clínicos pueden realizarse acuerdos de riesgo compartido por pacientes, que se enfoca en la participación activa del paciente en el manejo de su enfermedad y el monitoreo de su respuesta al tratamiento. El acuerdo puede incluir incentivos para que el paciente cumpla con el régimen de tratamiento y para reportar los resultados a los proveedores de atención médica. El acuerdo puede incluir también un reembolso parcial o total en caso de que el paciente no responda adecuadamente al tratamiento. Por otra parte los acuerdo de riesgo compartido por proveedores de atención médica, involucra a los proveedores de atención médica en el riesgo financiero del tratamiento. El fabricante acuerda proporcionar el medicamento a un precio reducido o con un reembolso parcial, y los proveedores de atención médica se comprometen a monitorear y reportar los resultados del tratamiento. Si los resultados no son los esperados, el fabricante proporciona un reembolso adicional. B. Acuerdos de cobertura con generación evidencia (CED): en estos acuerdos -los de mayor complejidad de implementación- se busca proporcionar cobertura a un nuevo medicamento o tecnología médica mientras se desarrollan estudios clínicos adicionales para confirmar su efectividad y seguridad. El objetivo es permitir el acceso a la tecnología en cuestión a los pacientes que lo necesitan mientras se recopilan datos adicionales. Vinculan el pago o el reembolso a nivel de población con la recolección de datos prospectiva de pacientes individuales. El acuerdo puede afectar a todos los pacientes candidatos a recibir la tecnología (llamados acuerdos sólo con investigación) o sólo a aquellos pacientes que sean incluidos voluntariamente en un ensayo clínico (denominados acuerdo sólo en investigación). En estos acuerdos se establece la cobertura del medicamento o tecnología a ciertos pacientes en base a ciertas condiciones. Por ejemplo, la cobertura puede estar limitada a pacientes con ciertas características o en determinadas etapas de la enfermedad. La cobertura se revisa regularmente y puede modificarse según los resultados de los ensayos clínicos adicionales. A continuación, se señalan algunos ejemplos de los distintos tipos de acuerdo18 Acuerdos basados en resultados financieros • Acuerdos por límite presupuestario Antivirales para Hepatitis C en Australia (desde 2015). El gobierno destinó un presupuesto anual para ser utilizado en estas drogas por encima del cual el productor de la tecnología reembolsaba la totalidad del costo por encima del mismo. • Acuerdos por límite de utilización Lenalidomida para el tratamiento de síndromes mielodisplásicos en UK. El gobierno paga hasta 26 ciclos del tratamiento, en aquellos pacientes que requieran más de 26 ciclos, los mismos son provistos por el productor de la tecnología sin costo. Acuerdos basados en resultados clínicos • Acuerdos de Reembolso vinculado a resultados (pago por resultados) Alfaglucosidada Alfa para Enfermedad de Pompe de desarrollo tardío en Estonia. El pago sólo se realiza ante aquellos pacientes con un resultado positivo confirmado por un panel de 4 médicos especialistas. • Acuerdos de cobertura con generación de evidencia Axicabtagene ciloleucel (Yescarta®) para el linfoma de células B en Inglaterra. El medicamento es cubierto por el Fondo de Drogas para el Cáncer (CDF) bajo la condición de generar más evidencia en torno a las estimaciones de supervivencia. La evidencia incluye un ensayo de fase II y la creación de un registro de cáncer. Al final del acuerdo, se vuelve a evaluar el medicamento y, si hay evidencia insuficiente o se considera que el medicamento no es clínicamente o económicamente efectivo, el medicamento puede ser eliminado del CDF y ya no estará disponible en el Servicio Nacional de Salud. En este caso, los pacientes seguirán recibiendo el medicamento que deberá ser pagado por el productor hasta que el médico prescriptor considere apropiado discontinuarlo. 45 18 Wenzl, M. and S. Chapman (2019), \"Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward\", OECD Health Working Papers, No. 115, OECD Publishing, Paris, https://doi. org/10.1787/6e5e4c0f-en.

b. Diferencias entre acuerdos financieros y acuerdos de Background Paper | Documento de base riesgo compartido ¿Cuándo elegir un acuerdo financiero o uno basado en resultados clínicos? La principal diferencia entre los acuerdos financieros y los basados en el desempeño radica en su enfoque. Los acuerdos financieros se centran en compartir la incertidumbre en relación al riesgo financiero y la forma en que se pagará un tratamiento permitiendo a los sistemas de salud precisar mejor los presupuestos sanitarios, mientras que los acuerdos basados en el desempeño se centran en la efectividad clínica del tratamiento y cómo se puede mejorar la calidad de la atención al paciente. Los acuerdos basados en resultados financieros son más fáciles de implementar que los acuerdos basados en resultados clínicos ya que requieren recolectar menor cantidad de datos y en general presentan menores dificultades para su monitoreo. La elección entre un acuerdo de riesgo basado en resultados clínicos o un acuerdo financiero dependerá del objetivo específico que se quiera alcanzar, de la incertidumbre en relación a la información clínica y del costo de la tecnología. Los acuerdos de riesgo basados en resultados clínicos se utilizan cuando los resultados clínicos o de salud no están claros o son inciertos, y se busca compartir el riesgo entre el fabricante y el pagador. Estos acuerdos se utilizan generalmente para productos nuevos o innovadores, o en situaciones en las que los resultados son impredecibles. Por otro lado, los acuerdos financieros se utilizan para lograr objetivos específicos de ahorro o de gestión de costos. Suelen aplicarse a productos que ya tienen un historial de resultados clínicos y de salud conocidos. La elección entre un acuerdo de riesgo basado en resultados clínicos y un acuerdo financiero dependerá de los objetivos específicos que se quieran alcanzar, así como de la naturaleza y el historial del medicamento o tratamiento en cuestión. 3.3 Descripción de su uso en los últimos años Castro et al. publicaron en 2019 una revisión de la literatura sobre Esquemas de Acceso a 46 Tecnologías19. Del total de acuerdos encontrados (n=285), el 95% de ellos habían sido realizados en países de altos ingresos (23 países europeos, 6 países asiáticos, 2 países en América del Norte, 2 en Oceanía y 1 en África). Los esquemas financieros eran más frecuentes que los basados en resultados clínicos (50,2% vs 44,9% respectivamente). Los acuerdos financieros fueron los más comunes en todo el mundo, mientras que los basados en desenlaces fueron más frecuentes en Norteamérica. Esto es coincidente con otros documentos que relevaron los distintos tipos de acuerdos realizados, donde en general son más frecuentes los acuerdos financieros que los basados en resultados clínicos.20 21 19 Castro, Hector & Malpica-Llanos, Tanya & Musila, Ruth & Konduri, Niranjan & Amaris, Ana & Sullivan, Jennifer & Gilmartin, Colin. (2019). Shar- ing knowledge for policy action in low- and middle-income countries: A literature review of managed entry agreements. Medicine Access Point of Care. 3. 239920261983424. 10.1177/2399202619834246. 20 Ferrario, A. and P. Kanavos (2013), Managed entry agreements for pharmaceuticals: The European experience, EMiNet, Brussels. 21 Wenzl, M. and S. Chapman (2019), \"Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward\", OECD Health Working Papers, No. 115, OECD Publishing, Paris,

Background Paper | Documento de base En cuanto a acuerdos de tipo financiero, un ejemplo es el Instituto Nacional de Excelencia en Salud y Atención (NICE) del Reino Unido que negocia con los productores para lograr niveles aceptables de costo-efectividad en los fármacos para los que brinda cobertura22 23. El rango del índice de costo- efectividad incremental (ICER) que generalmente se considera aceptable por NICE es de £20,000- 30,000 por año de vida ajustado por calidad (QALY) ganado y hasta £51,000/QALY ganado para los tratamientos de fin de vida. Un rango mucho más alto de ICER de £100,000-£300,000 se introdujo en 2017 para los medicamentos ultra huérfanos evaluados bajo la vía de tecnologías altamente especializadas (de su sigla en inglés Highly Specialized Treatments). NICE cuenta con Esquemas de Acceso al Paciente (de su sigla en inglés Patient Access Schemes) que en su mayoría constan de descuentos simples o de acuerdos comerciales basados en desempeño o en la generación de evidencia. El rango de descuentos negociados con NICE suele ser de entre el 30% y el 60%, siendo la mayoría de los descuentos dentro del rango del 45% al 50%. La falta de costo-efectividad probada debido a la incertidumbre de los datos clínicos o de otro tipo para el análisis económico, así como la incertidumbre relacionada con la eficacia relativa y la necesidad de recopilar más evidencia sobre los resultados a largo plazo y los efectos adversos del tratamiento son razones comunes para que NICE firme este tipo de acuerdos. Los medicamentos de terapia celular y génica (HST) tienen acuerdos basados en la financiación y la evaluación clínica, ya que la costo-efectividad siempre es incierta debido a las limitaciones de datos en las enfermedades raras. Además de las negociaciones del Fondo de Drogas para el Cáncer ( de su sigla en inglés Cancer Drugs Fund), el NHS de Inglaterra también está involucrado en discusiones de descuentos confidenciales con los fabricantes que conducen a un mayor ahorro en los costos. Un ejemplo de acuerdo basado en resultados, fué el implementado por NICE en relación a los medicamentos para Hepatitis C (Glecaprevir/Pibrentasvir Maviret® y Sofosbuvir Sovaldi®)24. Debido a su alto costo, los medicamentos antivirales de acción directa habían sido racionados por el NHS Inglaterra solo para pacientes seleccionados, a pesar de una recomendación positiva de NICE. Para manejar la presión pública y mejorar el acceso de los pacientes, el NHS Inglaterra firmó un acuerdo basado en resultados clínicos con los fabricantes en 2017. Bajo este acuerdo, el NHS sería reembolsado por los fabricantes el costo de los tratamientos de aquellos pacientes que habiendo completado su tratamiento no hubieran logrado una cura (respuesta virológica sostenida). Los pacientes fueron seguidos en un registro de hepatitis C para monitorear la adopción del tratamiento y los resultados y de esta manera poder calcular el reembolso. Otro ejemplo fué el realizado también por NICE en relación a Spinraza® (Nusinersen) en Atrofia Muscular Espinal (AME) donde se planteó un acuerdo con desarrollo de evidencia. En 2019, el NICE planteó varias preocupaciones en la evaluación de Spinraza, relacionadas con la recopilación de datos clínicos y de utilización de recursos25. Se firmó un acuerdo de cobertura con desarrollo de evidencia (de su sigla en inglés Coverage with Evidence Development) con el fabricante por cinco años, con un mínimo de tres años de recopilación de datos. Se acordó la realización final del reembolso al quinto año del esquema de CED. Se recopilaron varios puntos finales para el acuerdo de CED de distintas fuentes: estudios en curso, algunos registros como el SMA REACH UK, el sistema NHS Blueteq utilizado en UK para medicamentos de alto costo y las medidas de resultados reportados por los pacientes que se estaban desarrollando. Los datos se analizaron dos veces al año de acuerdo con un plan desarrollado por el fabricante. Los costos de recopilación y análisis de datos fueron sufragados por el fabricante. Este esquema está aún en curso. 47 22 Toumi, M., & Jarosławski, S. (2022). Managed Entry Agreements and Funding for Expensive Therapies. CRC Press. 23 Managed Access: Our Programmes. https://www.nice.org.uk/about/what-we-do/our-programmes/managed-access 24 25,000 Hepatitis C patients receive new treatment. https://www.england.nhs.uk/blog/25000-hepatitis-c-patients-receive-new-treatments/ 25 Facey KM, Espin J, Kent E, Link A, Nicod E, O'Leary A, Xoxi E, van de Vijver I, Zaremba A, Benisheva T, Vagoras A, Upadhyaya S. Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel. Pharmacoeconomics. 2021 Sep;39(9):1021-1044