Device innovation in cardiovascular medicine: a report from the European Society of Cardiology Cardiovascular Round Table.

Research performed in Europe has driven cardiovascular device innovation. This includes, but is not limited to, percutaneous coronary intervention, cardiac imaging, transcatheter heart valve implantation, and device therapy of cardiac arrhythmias and heart failure. An important part of future medical progress involves the evolution of medical technology and the ongoing development of artificial intelligence and machine learning. There is a need to foster an environment conducive to medical technology development and validation so that Europe can continue to play a major role in device innovation while providing high standards of safety. This paper summarizes viewpoints on the topic of device innovation in cardiovascular medicine at the European Society of Cardiology Cardiovascular Round Table, a strategic forum for high-level dialogue to discuss issues related to the future of cardiovascular health in Europe. Devices are developed and improved through an iterative process throughout their lifecycle. Early feasibility studies demonstrate proof of concept and help to optimize the design of a device. If successful, this should ideally be followed by randomized clinical trials comparing novel devices vs. accepted standards of care when available and the collection of post-market real-world evidence through registries. Unfortunately, standardized procedures for feasibility studies across various device categories have not yet been implemented in Europe. Cardiovascular imaging can be used to diagnose and characterize patients for interventions to improve procedural results and to monitor devices long term after implantation. Randomized clinical trials often use cardiac imaging-based inclusion criteria, while less frequently trials randomize patients to compare the diagnostic or prognostic value of different modalities. Applications using machine learning are increasingly important, but specific regulatory standards and pathways remain in development in both Europe and the USA. Standards are also needed for smart devices and digital technologies that support device-driven biomonitoring. Changes in device regulation introduced by the European Union aim to improve clinical evidence, transparency, and safety, but they may impact the speed of innovation, access, and availability. Device development programmes including dialogue on unmet needs and advice on study designs must be driven by a community of physicians, trialists, patients, regulators, payers, and industry to ensure that patients have access to innovative care.

Evidence from clinical trials on high-risk medical devices in children: a scoping review.

BACKGROUND: Meeting increased regulatory requirements for clinical evaluation of medical devices marketed in Europe in accordance with the Medical Device Regulation (EU 2017/745) is challenging, particularly for high-risk devices used in children. METHODS: Within the CORE-MD project, we performed a scoping review on evidence from clinical trials investigating high-risk paediatric medical devices used in paediatric cardiology, diabetology, orthopaedics and surgery, in patients aged 0-21 years. We searched Medline and Embase from 1st January 2017 to 9th November 2022. RESULTS: From 1692 records screened, 99 trials were included. Most were multicentre studies performed in North America and Europe that mainly had evaluated medical devices from the specialty of diabetology. Most had enrolled adolescents and 39% of trials included both children and adults. Randomized controlled trials accounted for 38% of the sample. Other frequently used designs were before-after studies (21%) and crossover trials (20%). Included trials were mainly small, with a sample size <100 participants in 64% of the studies. Most frequently assessed outcomes were efficacy and effectiveness as well as safety. CONCLUSION: Within the assessed sample, clinical trials on high-risk medical devices in children were of various designs, often lacked a concurrent control group, and recruited few infants and young children. IMPACT: In the assessed sample, clinical trials on high-risk medical devices in children were mainly small, with variable study designs (often without concurrent control), and they mostly enrolled adolescents. We provide a systematic summary of methodologies applied in clinical trials of medical devices in the paediatric population, reflecting obstacles in this research area that make it challenging to conduct adequately powered randomized controlled trials. In view of changing European regulations and related concerns about shortages of high-risk medical devices for children, our findings may assist competent authorities in setting realistic requirements for the evidence level to support device conformity certification.

Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

BACKGROUND AND AIMS: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. METHODS: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. RESULTS: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. CONCLUSIONS: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

Clinical investigations to evaluate high-risk orthopaedic devices: a systematic review of the peer-reviewed medical literature.

Purpose: The objective of this systematic review was to give an overview of clinical investigations regarding hip and knee arthroplasty implants published in peer-reviewed scientific medical journals before entry into force of the EU Medical Device Regulation in May 2021. Methods: We systematically reviewed the medical literature for a random selection of hip and knee implants to identify all peer-reviewed clinical investigations published within 10 years before and up to 20 years after regulatory approval. We report study characteristics, methodologies, outcomes, measures to prevent bias, and timing of clinical investigations of 30 current implants. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: We identified 2912 publications and finally included 151 papers published between 1995 and 2021 (63 on hip stems, 34 on hip cups, and 54 on knee systems). We identified no clinical studies published before Conformité Européene (CE)-marking for any selected device, and no studies even up to 20 years after CE-marking in one-quarter of devices. There were very few randomized controlled trials, and registry-based studies generally had larger sample sizes and better methodology. Conclusion: The peer-reviewed literature alone is insufficient as a source of clinical investigations of these high-risk devices intended for life-long use. A more systematic, efficient, and faster way to evaluate safety and performance is necessary. Using a phased introduction approach, nesting comparative studies of observational and experimental design in existing registries, increasing the use of benefit measures, and accelerating surrogate outcomes research will help to minimize risks and maximize benefits.

Placing patient-reported outcomes at the centre of cardiovascular clinical practice: implications for quality of care and management.

Patient-reported outcomes (PROs) provide important insights into patients' own perspectives about their health and medical condition, and there is evidence that their use can lead to improvements in the quality of care and to better-informed clinical decisions. Their application in cardiovascular populations has grown over the past decades. This statement describes what PROs are, and it provides an inventory of disease-specific and domain-specific PROs that have been developed for cardiovascular populations. International standards and quality indices have been published, which can guide the selection of PROs for clinical practice and in clinical trials and research; patients as well as experts in psychometrics should be involved in choosing which are most appropriate. Collaborations are needed to define criteria for using PROs to guide regulatory decisions, and the utility of PROs for comparing and monitoring the quality of care and for allocating resources should be evaluated. New sources for recording PROs include wearable digital health devices, medical registries, and electronic health record. Advice is given for the optimal use of PROs in shared clinical decision-making in cardiovascular medicine, and concerning future directions for their wider application.

In memoriam Liv Hatle 1936-2023, pioneering echocardiologist.

Professor Liv Hatle died in June 2023. In Trondheim, Norway, in the mid-1970s she was the first cardiologist to be given access to a PEDOF Doppler ultrasound system for clinical examinations, which she used to investigate cardiovascular haemodynamics non-invasively. She went on to establish methods for estimating valve gradients, pulmonary arterial pressure, and left ventricular diastolic function, that are still used today in millions of patients worldwide.

Quality and Utility of European Cardiovascular and Orthopaedic Registries for the Regulatory Evaluation of Medical Device Safety and Performance Across the Implant Lifecycle: A Systematic Review.

BACKGROUND: The European Union Medical Device Regulation (MDR) requires manufacturers to undertake post-market clinical follow-up (PMCF) to assess the safety and performance of their devices following approval and Conformité Européenne (CE) marking. The quality and reliability of device registries for this Regulation have not been reported. As part of the Coordinating Research and Evidence for Medical Devices (CORE-MD) project, we identified and reviewed European cardiovascular and orthopaedic registries to assess their structures, methods, and suitability as data sources for regulatory purposes. METHODS: Regional, national and multi-country European cardiovascular (coronary stents and valve repair/replacement) and orthopaedic (hip/knee prostheses) registries were identified using a systematic literature search. Annual reports, peer-reviewed publications, and websites were reviewed to extract publicly available information for 33 items related to structure and methodology in six domains and also for reported outcomes. RESULTS: Of the 20 cardiovascular and 26 orthopaedic registries fulfilling eligibility criteria, a median of 33% (IQR: 14%-71%) items for cardiovascular and 60% (IQR: 28%-100%) items for orthopaedic registries were reported, with large variation across domains. For instance, no cardiovascular and 16 (62%) orthopaedic registries reported patient/ procedure-level completeness. No cardiovascular and 5 (19%) orthopaedic registries reported outlier performances of devices, but each with a different outlier definition. There was large heterogeneity in reporting on items, outcomes, definitions of outcomes, and follow-up durations. CONCLUSION: European cardiovascular and orthopaedic device registries could improve their potential as data sources for regulatory purposes by reaching consensus on standardised reporting of structural and methodological characteristics to judge the quality of the evidence as well as outcomes.

European expert recommendations on clinical investigation and evaluation of high-risk medical devices for children.

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023. We developed recommendations for investigation of high-risk medical devices for children building on participants' expertise and results of a scoping review of clinical trials on high-risk medical devices in children. Approaches for evaluating and certifying high-risk medical devices for market introduction are proposed.

Artificial intelligence in medical device software and high-risk medical devices - a review of definitions, expert recommendations and regulatory initiatives.

INTRODUCTION: Artificial intelligence (AI) encompasses a wide range of algorithms with risks when used to support decisions about diagnosis or treatment, so professional and regulatory bodies are recommending how they should be managed. AREAS COVERED: AI systems may qualify as standalone medical device software (MDSW) or be embedded within a medical device. Within the European Union (EU) AI software must undergo a conformity assessment procedure to be approved as a medical device. The draft EU Regulation on AI proposes rules that will apply across industry sectors, while for devices the Medical Device Regulation also applies. In the CORE-MD project (Coordinating Research and Evidence for Medical Devices), we have surveyed definitions and summarize initiatives made by professional consensus groups, regulators, and standardization bodies. EXPERT OPINION: The level of clinical evidence required should be determined according to each application and to legal and methodological factors that contribute to risk, including accountability, transparency, and interpretability. EU guidance for MDSW based on international recommendations does not yet describe the clinical evidence needed for medical AI software. Regulators, notified bodies, manufacturers, clinicians and patients would all benefit from common standards for the clinical evaluation of high-risk AI applications and transparency of their evidence and performance.

Clinical evidence for high-risk medical devices used to manage diabetes: protocol for a systematic review and meta-analysis.

INTRODUCTION: Medical devices, including high-risk medical devices, have greatly contributed to recent improvements in the management of diabetes. However, the clinical evidence that is submitted for regulatory approval is not transparent, and thus a comprehensive summary of the evidence for high-risk devices approved for managing diabetes in Europe is lacking. In the framework of the Coordinating Research and Evidence for Medical Devices group, we will, therefore, perform a systematic review and meta-analysis, which will evaluate the efficacy, safety and usability of high-risk medical devices for the management of diabetes. METHOD AND ANALYSIS: This study has been reported according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will search Embase (Elsevier), Medline All (Ovid), Cochrane Library (Wiley), Science Citation Index Expanded and Emerging Sources Citation Index (Web of Science) to identify interventional and observational studies that evaluate the efficacy and/or safety and/or usability of high-risk medical devices for the management of diabetes. No language or publication dates' limits will be applied. Animal studies will be excluded. In accordance with the Medical Device Regulation in European Union, high-risk medical devices are those in classes IIb and III. The following medical devices for diabetes management are considered as having a high risk: implantable continuous glucose monitoring systems, implantable pumps and automated insulin delivery devices. Selection of studies, data extraction and quality of evidence assessment will be performed independently by two researchers. Sensitivity analysis will be performed to identify and explain potential heterogeneity. ETHICS AND DISSEMINATION: No ethical approval is needed for this systematic review, as it is based in already published data. Our findings will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022366871.

Validation of CORE-MD PMS Support Tool: A Novel Strategy for Aggregating Information from Notices of Failures to Support Medical Devices' Post-Market Surveillance.

INTRODUCTION: The EU Medical Device Regulation 2017/745 defines new rules for the certification and post-market surveillance of medical devices (MD), including an additional review by Expert Panels of clinical evaluation data for high-risk MD if reports and alerts suggest possibly associated increased risks. Within the EU-funded CORE-MD project, our aim was to develop a tool to support such process in which web-accessible safety notices (SN) are automatically retrieved and aggregated based on their specific MD categories and the European Medical Device Nomenclature (EMDN) classification by applying an Entity Resolution (ER) approach to enrich data integrating different sources. The performance of such approach was tested through a pilot study on the Italian data. METHODS: Information relevant to 7622 SN from 2009 to 2021 was retrieved from the Italian Ministry of Health website by Web scraping. For incomplete EMDN data (68%), the MD best match was searched within a list of about 1.5 M MD on the Italian market, using Natural Language Processing techniques and pairwise ER. The performance of this approach was tested on the 2440 SN (32%) already provided with the EMDN code as reference standard. RESULTS: The implemented ER method was able to correctly assign the correct manufacturer to the MD in each SN in 99% of the cases. Moreover, the correct EMDN code at level 1 was assigned in 2382 SN (97.62%), at level 2 in 2366 SN (96.97%) and at level 3 in 2329 SN (95.45%). CONCLUSION: The proposed approach was able to cope with the incompleteness of the publicly available data in the SN. In this way, grouping of SN relevant to a specific MD category/group/type could be used as possible sentinel for increased rates in reported serious incidents in high-risk MD.

A concise history of echocardiography: timeline, pioneers, and landmark publications.

Echocardiography is less than 70 years old, and many major advances have occurred within living memory, but already some pioneering contributions may be overlooked. In order to consider what circumstances have been common to the most successful innovations, we have studied and here provide a timeline and summary of the most important developments in transthoracic and transoesophageal ultrasound imaging and Doppler techniques, as well as in intravascular ultrasound and imaging in paediatric cardiology. The entries are linked to a comprehensive list of first publications and to a collection of first-hand historical accounts published by early investigators. Review of the original manuscripts highlights that it is difficult to establish unequivocal precedence for many new imaging methods, since engineers were often working independently but simultaneously on similar problems. Many individuals who are prominently linked with particular developments were not the first in their field. Developments in echocardiography have been highly dependent on technological advances, and most likely to be successful when engineers and clinicians were able to collaborate with open exchange between centres and disciplines. As with many other new medical technologies, initial responses were sceptical and introduction into clinical practice required persistence and substantial energy from the first adopters. Current developments involve advances in software as much as in equipment, and progress will depend on continuing collaborations between engineers and clinical scientists, for example to identify unmet needs and to investigate the clinical impact of particular imaging approaches.

History of Ultrasound in Medicine from its birth to date (2022), on occasion of the 50 Years Anniversary of EFSUMB. A publication of the European Federation of Societies for Ultrasound In Medicine and Biology (EFSUMB), designed to record the historical development of medical ultrasound.

The history of the European Federation of Societies in Ultrasound in Medicine and Biology (EFSUMB) is closely related to the general history of ultrasound. In the presented paper the physical background and history of technologies including A-mode, Time motion or M-mode, 2D Imaging (B-mode) are summarized. In addition, ultrasound tissue characterization, Doppler ultrasound, 3D and 4D ultrasound, intracavitary and endoscopic ultrasound, interventional ultrasound, ultrasonic therapy, contrast enhanced ultrasound (CEUS) and key developments in echocardiography are discussed.

Managing Incidental Findings Reported by Medical, Sonography and Other Students Performing Educational Ultrasound Examinations.

The evolution of ultrasound imaging into a key technology for diagnostic practice has resulted in its incorporation into the education of medical students worldwide. Although the introduction of ultrasound into medical schools' curricula is relatively recent, training of sonographers and other ultrasound users is mature. Ultrasound is being used in a variety of learning environments and clinical settings, from courses in anatomy and physiology to clinical rotations where medical and other students may scan healthy volunteers or patients, sometimes with little to no supervision. Educators may be apprehensive about a perceived high likelihood that students will encounter unexpected findings during these sessions, which could distress the patient or ultrasound model as well as the student, and result in problems that would be more pronounced if such incidental findings are complex. Policies are needed to address how to manage incidental ultrasound findings that are identified during educational activities. This article summarizes the background and provides a framework for establishing and implementing a well-designed and thoughtful approach for dealing with incidental findings observed in volunteer subjects by medical students during training courses in ultrasound diagnostic scanning. Subject confidentiality should be respected, and review of incidental findings should be transparent without provoking unnecessary anxiety. It is the responsibility of the instructor or supervisor to ensure adequate clinical follow-up if indicated.

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).

In the European Union (EU), the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, while authorising the placing on the market of medical devices is decentralised to independent 'conformity assessment' organisations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the Medical Device Directive, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details - which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024. Here, we describe how it may contribute to the development of regulatory science in Europe. Cite this article: EFORT Open Rev 2021;6:839-849. DOI: 10.1302/2058-5241.6.210081.

Implementation of the new EU IVD regulation - urgent initiatives are needed to avert impending crisis.

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&qid=1628781352814) to IVDR 2017/746 https://eur-lex.europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infrastructural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its "droit d'exister".