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.

A systematic review of the early dialogue frameworks used within health technology assessment and their actual adoption from HTA agencies.

Introduction: Early advice in the process of developing health technologies allows manufacturers to plan their production and transfer to health care systems more accurately. This review aims to describe frameworks used within HTA and their current use by HTA Agencies. Material and methods: We carried out a systematic literature review in Pubmed, Embase, Scopus, and WoS, including all references published in Spanish and English. This was last updated in March 2022. We extracted all available information regarding the organizations involved, services offered, types of technology, collaborators involved, fees, output and impact. Websites of several HTA organizations and Google were also searched in order to update and complete the information obtained from this generic search. Results: Five-hundred and forty one articles were identified and screened, of which 26 met the eligibility criteria and were selected. Seven of them were non-systematic reviews that described two or more HTA organizations. Ten studies were focused on the advice offered by individual organizations, and eight described the EMA and EUnetHTA parallel or joint advice. We found variations in the technology assessed, services offered, stage of development and costs for advisory services. Conclusions: Early and scientific advice would help manufacturers focus their product development on what is needed for the management of specific diseases. Most of the examples or services found refer to drugs as well as to some medical devices and diagnostics. A common definition of the type of advice that could be offered for different health technologies by HTA bodies to ascertain health care systems and manufacturers' needs, in addition to the timeline in which that advice needs to be given, would help HTA bodies provide the right support at the right time. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020219401, PROSPERO CRD42020219401.

Towards Better Pharmaceutical Provision in Europe-Who Decides the Future?

Significant progress has been achieved in human health in the European Union in recent years. New medicines, vaccines, and treatments have been developed to tackle some of the leading causes of disease and life-threatening illnesses. It is clear that investment in research and development (R&D) for innovative medicines and treatments is essential for making progress in preventing and treating diseases. Ahead of the legislative process, which should begin by the end of 2022, discussions focus on how Europe can best promote the huge potential benefits of new science and technology within the regulatory framework. The challenges in European healthcare were spelled out by the panellists at the roundtable organised by European Alliance for Personalised Medicine (EAPM). Outcomes from panellists' discussions have been summarized and re-arranged in this paper under five headings: innovation, unmet medical need, access, security of supply, adapting to progress, and efficiency. Some of the conclusions that emerged from the panel are a call for a better overall holistic vision of the future of pharmaceuticals and health in Europe and a collaborative effort among all stakeholders, seeing the delivery of medicines as part of a broader picture of healthcare.

A Proposal for Value-Based Managed Entry Agreements in an Environment of Technological Change and Economic Challenge for Publicly Funded Healthcare Systems.

Managed entry agreements (MEA) represent one of the main topics of discussion between the European National Payers Authorities. Several initiatives on the subject have been organized over the past few years and the scientific literature is full of publications on the subject. There is currently little international sharing of information between payers, mainly as a result of the confidentiality issues. There are potential benefits from the mutual sharing of information, both about the existence of MEAs and on the outcomes and results. The importance of involving all the players in the decision-making process on market access for a medicinal product (MP) is that it may help to make new therapies available to patients in a shorter time. The aim of this project is to propose a new pathway of value-based MEA (VBMEA), based on the analysis of the current Italian pricing and reimbursement framework. This requires elaboration of a transparent appraisal and MEA details with at least a 24-month contract. The price of the MP is therefore valued based on the analysis of the VBMEA registries of the Italian Medicines Agency. Although the proposal focuses on the Italian context, a similar approach could also be adapted in other nations, considering the particularities of the single health technology assessment (HTA)/payer system.

HTA Metro Map: a patient centred model for optimizing the decision making process.

Health Technology Assessment (HTA) is a systematic evaluation of a health technology, designed to appraise the direct or intended effects and indirect or unintended consequences of the technology with an overall goal of supporting informed decision making regarding the use of these health technologies in the healthcare system. In this paper, we present fundamental HTA concepts and provide a conceptual framework that embraces the processes and outcomes required for integrated healthcare decision-making. The "HTA Metro Map" was designed to guide the user through the different areas on: where to use, what and whom to involve within the decision process. The map reflects the complexity and inter-connectedness of the different kind of healthcare services that need to work together to be able to efficiently deliver coordinated decisions at local, regional, national, and international levels. This tool may also serve as base for facilitating developments and improvements of the HTA structure worldwide. The paper discusses the main features of the "HTA Metro Map" while reinforcing the key concepts underlying HTA's integrated approach. The first view of the map provides the several layers of complexity seen in HTA and the various lines within the map represent the main actors involved in the assessment processes. The map connections and crossings symbolize the interprofessional and interpersonal collaborations while the stations denote the knowledge, skills, experiences, and attitudes of each professionals as they interact within this framework. Every line represents a HTA stakeholder and the circular line in the centre represents the patient at the centre of the system. The zones, from social to community and hospital level, represent the need for integration from the perspective of health systems. The HTA Metro Map also has different dimensions depicted by the level of profoundness. Finally, the concepts of different healthcare stakeholder perspectives are introduced both in visual and temporal terms. The "HTA Metro Map" is designed as a flexible model for easy adaptability and in accurately capturing the complexity inherent in any healthcare system. It is hoped that the map will assist different stakeholders to build network capacity, pool existing resources, and develop a more holistic vision that will result in a sustainable, efficient and collaborative decision-making process.

[ICHI-International Classification of Health Interventions : A balancing act between the demands of statistics and reimbursement]. / ICHI ­ International Classification of Health Interventions : Prozedurenklassifikation im Spagat zwischen Statistik und Abrechnung.

Medical classifications systematize medical concepts (e. g. diagnoses, procedures). They are essential for statistics and reimbursement systems in health care systems. Diagnoses are classified worldwide with the International Classification of Diseases (ICD) of the World Health Organization (WHO). The situation for procedure classifications is quite different. Many countries developed their own procedure classifications in different ways and for different purposes.Since 2007, the International Classification of Health Interventions (ICHI) is been developing as a common tool for reporting and analyzing health interventions for statistical purposes as well as for the use in reimbursement systems.ICHI covers not only medical and surgical procedures but also interventions carried out by a broad range of providers across the full scope of health systems, including rehabilitation, assistance with functioning, prevention and public health.The multiaxial classification is built around three axes: target (the entity on which the action is carried out), action (a deed done by an actor to a target) and means (the processes and methods by which the action is carried out). Extension codes are provided to allow users to describe additional detail about the intervention in addition to the relevant ICHI stem-code. ICHI was designed with a low level of complexity for countries seeking a classification, while also serving as a basis for international comparisons. ICHI can also be used in reimbursement systems, by adding cost-relevant information through extension codes.The recent 2018 ICHI beta version is available on the platform https://mitel.dimi.uniud.it/ichi . This version and further ICHI tools will be tested during later reviews and field testing in 2018 and 2019. Once finalized, probably in 2020, ICHI will be freely available for adoption by member states of the WHO.

Supporting decision making in cross-border regions: a health technology assessment tool for hospitals.

OBJECTIVES: The aim of this study was to develop an health technology assessment (HTA) decision tool to support the decision-making process on health technologies for hospital decision makers in cross-border regions. METHODS: Several methods were used to collect information necessary to develop the cross-border mini-HTA decision tool. The literature was inventoried on HTA in border regions and local settings and the use of HTA by local decision makers. Semi-structured interviews with hospital decision makers in cross-border regions were also performed. Based on group discussion of the resulting information, it was decided to use the Danish mini-HTA guideline as a starting point for development of the decision tool. After finishing the first version of the decision tool it was tested in two pilot studies. RESULTS: Some questions in the Danish mini-HTA guideline were not relevant. Other questions needed rephrasing and questions about cross-border situations were added. The pilots showed several missing topics, including legal questions and reimbursement issues. The final decision tool consists of three sections: a general section, a section for hospitals not cooperating cross-border and a section for hospitals that are cooperating with hospitals across a national or regional border. CONCLUSIONS: Based on our literature search, this may be the first cross-border mini-HTA decision tool. The decision tool will be of help for healthcare professionals and decision makers in border settings who would like to use HTA evidence to support their decision-making process.

The Learning-Adapting-Leveling model: from theory to hypothesis of steps for implementation of basic genome-based evidence in personalized medicine.

We see a backlog in the effective and efficient integration of personalized medicine applications such as genome-based information and technologies into healthcare systems. This article aims to expand on the steps of a published innovative model, which addresses the bottleneck of real-time integration into healthcare. We present a deconstruction of the Learning-Adapting-Leveling model to simplify the steps. We found out that throughout the technology transfer pipeline, contacts, assessments and adaptations/feedback loops are made with health needs assessment, health technology assessment and health impact assessment professionals in the same order by the academic-industrial complex, resulting in early-on involvement of all stakeholders. We conclude that the model steps can be used to resolve the bottleneck of implementation of personalized medicine application into healthcare systems.

EAES recommendations on methodology of innovation management in endoscopic surgery.

BACKGROUND: Under the mandate of the European Association for Endoscopic Surgery (EAES) a guideline on methodology of innovation management in endoscopic surgery has been developed. The primary focus of this guideline is patient safety, efficacy, and effectiveness. METHODS: An international expert panel was invited to develop recommendations for the assessment and introduction of surgical innovations. A consensus development conference (CDC) took place in May 2009 using the method of a nominal group process (NGP). The recommendations were presented at the annual EAES congress in Prague, Czech Republic, on June 18th, 2009 for discussion and further input. After further Delphi processes between the experts, the final recommendations were agreed upon. RESULTS: The development and implementation of innovations in surgery are addressed in five sections: (1) definition of an innovation, (2) preclinical and (3) clinical scientific development, (4) scientific approval, and (5) implementation along with monitoring. Within the present guideline each of the sections and several steps are defined, and several recommendations based on available evidence have been agreed within each category. A comprehensive workflow of the different steps is given in an algorithm. In addition, issues of health technology assessment (HTA) serving to estimate efficiency followed by ethical directives are given. CONCLUSIONS: Innovations into clinical practice should be introduced with the highest possible grade of safety for the patient (nil nocere: do no harm). The recommendations can contribute to the attainment of this objective without preventing future promising diagnostic and therapeutic innovations in the field of surgery and allied techniques.