Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Failure due to formal reasons within German benefit assessment of medicinal products: the dilemma between marketing authorization and HTA.

Objective: Due to the impact of the Federal Joint Committee's (FJC) appraisal on following price negotiations, it is crucial to understand the underlying reasons of failure in early benefit assessment (EBA) of medicinal products in Germany. Methods: Medicinal products for which no added benefit was granted, the underlying reasons given by the FJC were extracted and grouped into respective categories according to predefined working definitions. Several reasons may hold for one subgroup. Furthermore, binomial proportion analysis was performed to gather proportions and their precision for each therapeutic area regarding possible failure. Results: 293/427 subgroups did not receive an added benefit. For 265/293 the following main formal reasons were stated: deviation of label to the pivotal studies (59%), wrong comparator (20.5%), and methodological deficiencies of indirect comparisons (12.3%). The proportion of failure in EBA is heterogeneous and therapeutic area depending (p = 0.0005). For most of the therapeutic areas, the confidence intervals of binomial proportions include 50%. Conclusion: Various different reasons led to the failure of EBAs in the past. Despite different objectives, a better alignment between the requirements and methods in the marketing authorization procedure and the EBA might facilitate the design of pivotal studies, which may be useful in both procedures.

Development of a decisional flowchart for meaningful patient involvement in Health Technology Assessment.

INTRODUCTION: This paper aims to describe the development of a flowchart to guide the decisions of researchers in the Spanish Network for Health Technology Assessment of the National Health System (RedETS) regarding patient involvement (PI) in Health Technology Assessment (HTA). By doing so, it reflects on current methodological challenges in PI in the HTA field: how best to combine PI methods and what is the role of patient-based evidence. METHODS: A decisional flowchart for PI in HTA was developed between March and April 2019 following an iterative process, reviewed by the members of the PI Interest Group and other RedETS members and validated during an online deliberative meeting. The development of the flowchart was based on a previous methodological framework assessed in a pilot study. RESULTS: The guidelines on how to involve patients in HTA in the RedETS were graphically represented in a flowchart. PI must be included in all HTA reports, except those that assess technologies with no relevant impact on patients' experiences, values, and preferences. Patient organizations or expert patients related to the topic of the HTA report must be identified and invited. These patients can participate in protocol development, outcomes' identification, assessment process, and report review. When the technology assessed affects in a relevant way patient experiences, values, and preferences, patient-based evidence should be included through a systematic literature review or a primary study. CONCLUSIONS: The decisional flowchart for PI in HTA contributes to the current methodological challenges by proposing a combination of direct involvement and patient-based evidence.

Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations.

To maintain orphan drug status at the time of market authorization, orphan medicinal products (OMPs) need to be assessed for all criteria, including significant benefit, by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). Subsequently, health technology assessment (HTA) organizations evaluate the same OMPs in their relative effectiveness assessments (REAs). This review investigates the similarities and differences between the two frameworks for six HTA organizations, including the European Network for HTA. We discuss differences between both assessment frameworks within five domains (clinical evidence used, patient population, intervention, comparators, and outcome measures) for all drugs. Five illustrative cases studies were selected for a qualitative review.

Health Technology Assessment (HTA) and Access Policies.

For patients, innovations in healthcare can be both a great blessing (when saving people's life or improving quality of life), as well as a curse (when only few people have access, e.g., because of high prices). Thus, when healthcare innovations are proven safe and ready for application, decision makers have to apply access policies and sometimes face difficult assessments. In this context, health technology assessment (HTA) plays a crucial role at European Union level, forming an evidence-based, transparent basis for decision making through joint assessments. However, pricing and reimbursement aspects are exempt from collaborative assessments, since these are in the responsibility of the EU Member States: according to Art. 168(7) TFEU the 'organisation and delivery of health services and medical care [… including] the allocation of the resources assigned to them' remain an exclusive competence of Member States. However, future challenges may require further cooperation.

Picturing ELSI+: a visual representation of ethical, legal, and social issues, and patient experiences in Health Technology Assessment in Canada.

OBJECTIVES: Consideration of ethical, legal, and social issues plus patient values (ELSI+) in health technology assessment (HTA) is challenging because of a lack of conceptual clarity and the multi-disciplinary nature of ELSI+. We used concept mapping to identify key concepts and inter-relationships in the ELSI+ domain and provide a conceptual framework for consideration of ELSI+ in HTA. METHODS: We conducted a scoping review (Medline and EMBASE, 2000-2016) to identify ELSI+ issues in the HTA literature. Items from the scoping review and an expert brainstorming session were consolidated into eighty ELSI+-related statements, which were entered into Concept Systems® Global MAX™ software. Participants (N = 38; 36 percent worked as researchers, 21 percent as academics; 42 percent self-identified as HTA experts) sorted the statements into thematic groups, and rated them on importance in making decisions about adopting technologies in Canada, from 1 (not at all important) to 5 (extremely important). We used Concept Systems® Global MAX™ software to create and analyze concept maps with four to sixteen clusters. RESULTS: Our final ELSI+ map consisted of five clusters, with each cluster representing a different concept and the statements within each cluster representing the same concept. Based on the concepts, we named these clusters: patient preferences/experiences, patient quality of life/function, patient burden/harm, fairness, and organizational. The highest mean importance ratings were for the statements in the patient burden/harm (3.82) and organizational (3.92) clusters. CONCLUSIONS: This study suggests an alternative approach to ELSI+, based on conceptual coherence rather than academic disciplines. This will provide a foundation for incorporating ELSI+ into HTA.

Mapping the rise of digital mental health technologies: Emerging issues for law and society.

The use of digital technologies in mental health initiatives is expanding, leading to calls for clearer legal and regulatory frameworks. However, gaps in knowledge about the scale and nature of change impede efforts to develop responsible public governance in the early stages of what may be the mass uptake of 'digital mental health technologies'. This article maps established and emerging technologies in the mental health context with an eye to locating major socio-legal issues. The paper discusses various types of technology, including those designed for information sharing, communication, clinical decision support, 'digital therapies', patient and/or population monitoring and control, bio-informatics and personalised medicine, and service user health informatics. The discussion is organised around domains of use based on the actors who use the technologies, and those on whom they are used. These actors go beyond mental health service users and practitioners/service providers, and include health and social system or resource managers, data management services, private companies that collect personal data (such as major technology corporations and data brokers), and multiple government agencies and private sector actors across diverse fields of criminal justice, education, and so on. The mapping exercise offers a starting point to better identify cross-cutting legal, ethical and social issues at the convergence of digital technology and contemporary mental health practice.

Supervisión de ensayos clínicos en hospitales del Seguro Social de Salud del Perú: enfoque administrativo y regulatorio / Supervision of clinical trials in Social Health Insurance at Peruvian Hospitals: administrative and regulatory approach

RESUMEN El objetivo del estudio fue describir las características de los ensayos clínicos (EC) supervisados por el Instituto de Evaluación de Tecnologías en Salud e Investigación en EsSalud entre el 2015 y 2018 y las principales observaciones de las supervisiones realizadas. Se realizó un estudio descriptivo de 82 ensayos clínicos supervisados entre 2015 y 2018. La mayoría de los ensayos clínicos fueron estudios de fase III (81,7%), la vía de administración más frecuente de los productos de estudio fue oral (47,6%) y la mayoría fueron patrocinados por la industria farmacéutica (96,3%). Las observaciones más frecuentes fueron las relacionadas al contrato de estudio (83,8%), al pago por concepto de overhead (57,3%) y a la falta de documentos regulatorios (47,6%). Estos hallazgos permiten la identificación de oportunidades de mejora en la regulación y gestión de la investigación.

ABSTRACT The objective of the study was to describe the characteristics of the Clinical Trials (CT) supervised by the Institute of Health Technology Assessment and Research carried out in EsSalud between 2015 and 2018 and the main observations of the supervisions completed. A descriptive study of 82 supervised clinical trials was conducted between 2015 and 2018. Most of the clinical trials were phase III studies (81.7%); the most frequent route of administration of the study products was oral (47.6%), and most were sponsored by the pharmaceutical industry (96.3%). The most frequent observations were those related to the study contract (83.8%), overhead payment (57.3%), and the lack of regulatory documents (47.6%). These findings allow the identification of opportunities for improvement in research regulation and management.

[The incorporation of nusinersen by the Brazilian Unified National Health System: critical thoughts on the institutionalization of health technology assessment in Brazil]. / A incorporação do nusinersena no Sistema Único de Saúde: uma reflexão crítica sobre a institucionalização da avaliação de tecnologias em saúde no Brasil.

In April 2019, a ruling was signed for the incorporation of the drug nusinersen by the Brazilian Unified National Health System (SUS). Nusinersen is the most expensive drug ever incorporated by the SUS and is used to treat type I 5q spinal muscular atrophy. The incorporation has been described as a milestone in decision-making on new technologies in the SUS, enabled through a risk-sharing agreement. The article discusses the process involved in the incorporation of nusinersen, highlighting the context, timing, and technical issues, in addition to possible consequences for the institutionalization of health technology assessment (HTA) in the SUS. The study used an exploratory method, reviewing public information produced by the Commission for Incorporation of Technologies in the SUS (CONITEC) and searches in government databanks on prices and purchases. A timeline was produced, describing the key points in the process of incorporation. There were two formal requests for the drug's incorporation. The first was submitted by the Division of Science, Technology, and Strategic Inputs (SCTIE) of the Brazilian Ministry of Health and was turned down unanimously in November 2018. This was followed by a petition by the head of the SCTIE to the Attorney General's Office (AGU) to overrule the recommendation by the CONITEC plenary. The AGU recommended a new submission, made by the drug's manufacturing company, which was approved unanimously in March 2019. The was no addition of new evidence or a price reduction to justify the change of decision. No elements were identified in the risk-sharing agreement. This suggests problems of transparency and accountability, as well as risks in the process of institutionalization of HTA that had been underway in the SUS.

Em abril de 2019, foi assinada a portaria de incorporação do medicamento nusinersena no Sistema Único de Saúde (SUS). É o medicamento mais caro já incorporado ao SUS, para uso no tratamento de atrofia muscular espinhal 5q tipo I. A incorporação é referida como um marco na tomada de decisão sobre novas tecnologias no SUS, a ser viabilizada por meio de acordo de partilha de risco. O trabalho discute o processo de incorporação do nusinersena, destacando aspectos contextuais, temporais e técnicos, além de possíveis consequências para a institucionalização da avaliação de tecnologias em saúde (ATS) no SUS. Seguiu método exploratório, com revisão de informações públicas produzidas pela Comissão de Incorporação de Tecnologias no SUS (CONITEC) e busca em bancos de dados governamentais de preços e compras. Foi produzida linha temporal descrevendo os pontos-chave do processo de incorporação. Houve dois pedidos de incorporação do medicamento. O primeiro, submetido pela Secretaria de Ciência, Tecnologia e Insumos Estratégicos (SCTIE) do Ministério da Saúde, negado por unanimidade, em novembro de 2018. Seguiu-se o pedido do Secretário da SCTIE à Advocacia-Geral da União (AGU), para que pudesse decidir de forma contrária à recomendação do plenário da CONITEC. A AGU recomendou uma nova submissão, feita pela empresa produtora e aprovada por unanimidade, em março de 2019. Não houve acréscimo de novas evidências ou redução de preço que justificassem a mudança de decisão. Não foram identificados os elementos constituintes do acordo de partilha de risco. São sinalizados problemas de transparência e accountability, bem como riscos ao processo de institucionalização da ATS que vinha em curso no SUS.

Resumen: En abril de 2019, se firmó el decreto de incorporación del medicamento nusinersén en el Sistema Único de Salud brasileño (SUS). Es el medicamento más caro que se ha incorporado al SUS para su uso en el tratamiento de la atrofia muscular espinal 5q tipo I. La incorporación del mismo está considerada como un marco de referencia en la toma de decisiones sobre nuevas tecnologías en el SUS, que puede ser viable mediante el acuerdo de distribución de riesgo. El trabajo discute el proceso de incorporación del nusinersén, destacando aspectos contextuales, temporales y técnicos, además de posibles consecuencias para la institucionalización de la evaluación de tecnologías en salud (ETS) en el SUS. El trabajo siguió el método exploratorio, con una revisión de la información pública, generada por la Comisión de Incorporación de Tecnologías en el SUS (CONITEC) y la búsqueda en bancos de datos gubernamentales de precios y compras. Se creó una línea temporal, describiendo los puntos-clave del proceso de incorporación. Hubo dos peticiones de incorporación del medicamento. La primera, sometida a la Secretaría de Ciencia, Tecnología e Insumos Estratégicos (SCTIE) del Ministerio de Salud, rechazada por unanimidad, en noviembre de 2018. A lo que le siguió la petición del Secretario de la SCTIE a la Abogacía-General de la Unión (AGU), para que pudiese decidir en otro sentido respecto a la recomendación del pleno de la CONITEC. La AGU recomendó una nueva remisión, realizada por la empresa productora y aprobada por unanimidad, en marzo de 2019. No se produjo un incremento de nuevas evidencias o una reducción del precio que justificasen el cambio de decisión. No se identificaron los elementos constituyentes del acuerdo de distribución de riesgo. Se señalaron los problemas de transparencia y rendición de cuentas, así como riesgos para el proceso de institucionalización de la ETS que estaba en curso en el SUS.

Conditional Financing of Drugs in the Netherlands: Past, Present, and Future-Results From Stakeholder Interviews.

BACKGROUND: Conditional financing (CF) of hospital drugs was implemented in the Netherlands as a form of managed entry agreements between 2006 and 2012. CF was a 4-year process comprising 3 stages: initial health technology assessment of the drug (T = 0), conduct of outcomes research studies, and reassessment of the drug (T = 4). OBJECTIVES: To analyze stakeholder experiences in implementing CF in practice. METHODS: Public and private stakeholders were approached for participation in stakeholder interviews through standardized email invitations. An interview guide was developed to guide discussions that covered the following topics: perceived aims of CF, functioning of CF, impact of CF, and conclusions and future perspectives. Extensive summaries were generated for each interview and subsequently used for directed content analysis. RESULTS: Thirty stakeholders were interviewed. Differences emerged among the stakeholders on the perceived aims of CF. Conversely, there was some agreement among stakeholders on the shortcomings in the functioning of CF, the positive impact of CF on the Dutch healthcare setting, and improvement points for CF. CONCLUSIONS: Despite stakeholders' belief that CF either did not meet its aims or only partially did so, there was agreement on the need for new policy to address the same aims of CF in the future. Nevertheless, stakeholders diverged on whether CF should be improved on the basis of learnings identified and reintroduced into practice or replaced with new policy schemes.

Historical overview of regulatory framework development on pricing and reimbursement of medicines in Bulgaria.

Objectives: The current study aims to analyze, from a historical perspective, the regulatory framework of prices and reimbursement in Bulgaria with emphasis on the introduction of economic evaluation.Methods: The study explores all regulatory changes during the period 1995-2016 combining the macroeconomic and regulatory analysis on medicines pricing and reimbursement. A roadmap summarizing the current regulatory requirements for the medicinal product entrance on national market and access to public funding was elaborated.Results: Demographic processes in the country have been negative for the past decade. On the other hand, health care and pharmaceutical expenditures experienced a growth up to 8.6% and 3% of total GDP, respectively. The total pharmaceutical market permanently grew from 309 to 1409 million of Euro. During the last 20 years, the pricing and reimbursement legislation of medicines in Bulgaria was changed extensively.Conclusion: Pricing policy remains oriented toward the lowest European prices and reimbursement policy impose cost containment measures. Appraisal of the obligatory Health Technology Assessment Dossiers and pharmacoeconomic analysis is in accordance with world recommendations. Main regulatory issues that still remain to be tackled are the slower entrance of medicines on the national market and lower national prices that often lead to parallel import.

Proposal for a regulation on health technology assessment in Europe - opinions of policy makers, payers and academics from the field of HTA.

INTRODUCTION: In January 2018 the European Commission published a Proposal for a Regulation on Health Technology Assessment (HTA): 'Proposal for a Regulation on health technology assessment and amending Directive 2011/24/EU'. A number of stakeholders, including some Member States, welcomed this initiative as it was considered to improve collaboration, reduce duplication and improve efficiency. There were however a number of concerns including its legal basis, the establishment of a single managing authority, the preservation of national jurisdiction over HTA decision-making and the voluntary/mandatory uptake of joint assessments by Member States. Areas covered: This paper presents the consolidated views and considerations on the original Proposal as set by the European Commission of a number of policy makers, payers, experts from pricing and reimbursement authorities and academics from across Europe. Expert commentary: The Proposal has since been extensively discussed at Council and while good progress has been achieved, there are still divergent positions. The European Parliament gave a number of recommendations for amendments. If the Proposal is approved, it is important that a balanced, improved outcome is achieved for all stakeholders. If not approved, the extensive contribution and progress attained should be sustained and preserved, and the best alternative solutions found.

Model-Informed Drug Development: Current US Regulatory Practice and Future Considerations.

Model-informed drug development (MIDD) refers to the application of a wide range of quantitative models in drug development to facilitate the decision-making process. MIDD was formally recognized in Prescription Drug User Fee Act (PDUFA) VI. There have been many regulatory applications of MIDD to address a variety of drug development and regulatory questions. These applications can be broadly classified into four categories: dose optimization, supportive evidence for efficacy, clinical trial design, and informing policy. Case studies, literature papers, and published regulatory documents are reviewed in this article to highlight some common features of these applications in each category. In addition to the further development and investment in these established domains of application, new technology, and areas, such as more mechanistic models, neural network models, and real-world data/evidence, are gaining attention, and more submissions and experiences are being accumulated to expand the application of model-based analysis to a wider scope.

[Supervision of clinical trials in Social Health Insurance at Peruvian Hospitals: administrative and regulatory approach]. / Supervisión de ensayos clínicos en hospitales del Seguro Social de Salud del Perú: enfoque administrativo y regulatorio.

The objective of the study was to describe the characteristics of the Clinical Trials (CT) supervised by the Institute of Health Technology Assessment and Research carried out in EsSalud between 2015 and 2018 and the main observations of the supervisions completed. A descriptive study of 82 supervised clinical trials was conducted between 2015 and 2018. Most of the clinical trials were phase III studies (81.7%); the most frequent route of administration of the study products was oral (47.6%), and most were sponsored by the pharmaceutical industry (96.3%). The most frequent observations were those related to the study contract (83.8%), overhead payment (57.3%), and the lack of regulatory documents (47.6%). These findings allow the identification of opportunities for improvement in research regulation and management.

El objetivo del estudio fue describir las características de los ensayos clínicos (EC) supervisados por el Instituto de Evaluación de Tecnologías en Salud e Investigación en EsSalud entre el 2015 y 2018 y las principales observaciones de las supervisiones realizadas. Se realizó un estudio descriptivo de 82 ensayos clínicos supervisados entre 2015 y 2018. La mayoría de los ensayos clínicos fueron estudios de fase III (81,7%), la vía de administración más frecuente de los productos de estudio fue oral (47,6%) y la mayoría fueron patrocinados por la industria farmacéutica (96,3%). Las observaciones más frecuentes fueron las relacionadas al contrato de estudio (83,8%), al pago por concepto de overhead (57,3%) y a la falta de documentos regulatorios (47,6%). Estos hallazgos permiten la identificación de oportunidades de mejora en la regulación y gestión de la investigación.

The Confluence of Accelerated Regulatory and Health Technology Assessment Access Pathways.

There is a growing interest in aligning accelerated regulatory pathways with flexible access and reimbursement pathways to expedite the equitable availability of high-quality, safe, and effective medicines that provide a value-based approach to meeting society's most important healthcare needs. The Centre for Innovation in Regulatory Science (CIRS) identified key issues regarding the confluence of regulatory and health technology assessment processes from discussions and presentations given by international regulators, health technology assessment bodies, payers, patient representatives, and multinational pharmaceutical company representatives on this topic at CIRS workshops held in 2014 and 2017 that focused on the commonalties and differences across these pathways. Recent publications have also been highlighted. The barriers to and opportunities for aligning stakeholder expectations and needs were investigated and recommendations provided. Early dialogue among the stakeholders is the process that will likely provide the greatest return on investment of time and effort to identify, develop, review, and recommend important new medicines, especially those that address an unmet medical need.

Data Rich, Information Poor: Can We Use Electronic Health Records to Create a Learning Healthcare System for Pharmaceuticals?

Judicious use of real-world data (RWD) is expected to make all steps in the development and use of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing, and reimbursement decisions and treatment. A "learning healthcare system" based on electronic health records and other routinely collected data will be required to harness the full potential of RWD to complement evidence based on randomized controlled trials. We describe and illustrate with examples the growing demand for a learning healthcare system; we contrast the exigencies of an efficient pharmaceutical ecosystem in the future with current deficiencies highlighted in recently published Organisation for Economic Co-operation and Development (OECD) reports; and we reflect on the steps necessary to enable the transition from healthcare data to actionable information. A coordinated effort from all stakeholders and international cooperation will be required to increase the speed of implementation of the learning healthcare system, to everybody's benefit.