Principles of ideal diagnostic regulation and the IVDR.

This article discusses principles and concepts for ideal regulatory frameworks for diagnostics, and the expression of those principles in the EU IVDR. The authors present the benefits of regulatory frameworks and implementation approaches for diagnostics that are risk-based, globally convergent, connected, nimble and efficient, under the IVDR and with a future outlook. While many expressions of these principles can already be found in the EU IVDR text, and in its implementation approaches, their further embrace is needed in future EU diagnostic regulation. In the long term outlook, risk-based approaches can be extended to comprise entity-based excellence appraisals. Globally convergent approaches can be more explicit in e.g. qualification and classification of products. This will also help further reliance models. Better connections and cooperation between regulators across the healthcare spectrum including pharmaceuticals should be fostered. Nimble approaches such as Emergency Use Authorisations for pandemics are essential in highly regulated schemes like the IVDR and beyond. Finally, regulatory efficiency as in timely availability of IT infrastructure and oversight mechanisms is a distinguishing attribute of globally competitive diagnostic regulatory schemes. All the above needs consideration in the long term efforts to modernize the EU regulatory system, so that diagnostics can play their important role in clinical research as well as along the entire care continuum in the EU.

The Difference between Approval Processes for Medicinal Products and Medical Devices in Europe.

The approval of new ophthalmic medical devices and medicinal products is governed by separate processes in Europe with different requirements, classifications, and timelines involved. For pharmaceuticals, companies can go through a centralized European-level process working with the European Medicines Agency (EMA) or a decentralized procedure working with a member state competent authority to gain approval or via mutual recognition. For medical devices, companies must work with a European Union approved Notified Body as there is no equivalent to the EMA. With medicinal products, approval can be sought as a new medicinal product, generic, known substance, or as an advanced therapy. With medical devices, the classifications are based on the use and complexity of the device as well as the risk, beginning with class I (surgical instruments and some diagnostic devices), to class IIA, class IIB, and class III, which are the most invasive devices, such as pacemakers and breast implants. From May 2021, the European Union will fully implement the Medical Device Regulation, which enforces increased requirements before class IIa and above devices can be CE marked. This process for approving medical devices and pharmaceuticals in Europe is designed to ensure that new technology is thoroughly vetted before becoming commercially available.

Comparative sensitivity evaluation for 122 CE-marked rapid diagnostic tests for SARS-CoV-2 antigen, Germany, September 2020 to April 2021.

IntroductionNumerous CE-marked SARS-CoV-2 antigen rapid diagnostic tests (Ag RDT) are offered in Europe, several of them with unconfirmed quality claims.AimWe performed an independent head-to-head evaluation of the sensitivity of SARS-CoV-2 Ag RDT offered in Germany.MethodsWe addressed the sensitivity of 122 Ag RDT in direct comparison using a common evaluation panel comprised of 50 specimens. Minimum sensitivity of 75% for panel specimens with a PCR quantification cycle (Cq) ≤ 25 was used to identify Ag RDT eligible for reimbursement in the German healthcare system.ResultsThe sensitivity of different SARS-CoV-2 Ag RDT varied over a wide range. The sensitivity limit of 75% for panel members with Cq ≤ 25 was met by 96 of the 122 tests evaluated; 26 tests exhibited lower sensitivity, few of which failed completely. Some RDT exhibited high sensitivity, e.g. 97.5 % for Cq < 30.ConclusionsThis comparative evaluation succeeded in distinguishing less sensitive from better performing Ag RDT. Most of the evaluated Ag RDT appeared to be suitable for fast identification of acute infections associated with high viral loads. Market access of SARS-CoV-2 Ag RDT should be based on minimal requirements for sensitivity and specificity.

Diabetes digital app technology: benefits, challenges, and recommendations. A consensus report by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) Diabetes Technology Working Group.

Digital health technology, especially digital and health applications ('apps'), have been developing rapidly to help people manage their diabetes. Numerous health-related apps provided on smartphones and other wireless devices are available to support people with diabetes who need to adopt either lifestyle interventions or medication adjustments in response to glucose-monitoring data. However, regulations and guidelines have not caught up with the burgeoning field to standardise how mobile health apps are reviewed and monitored for patient safety and clinical validity. The available evidence on the safety and effectiveness of mobile health apps, especially for diabetes, remains limited. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have therefore conducted a joint review of the current landscape of available diabetes digital health technology (only stand-alone diabetes apps, as opposed to those that are integral to a regulated medical device, such as insulin pumps, continuous glucose monitoring systems, and automated insulin delivery systems) and practices of regulatory authorities and organisations. We found that, across the USA and Europe, mobile apps intended to manage health and wellness are largely unregulated unless they meet the definition of medical devices for therapeutic and/or diagnostic purposes. International organisations, including the International Medical Device Regulators Forum and WHO, have made strides in classifying different types of digital health technology and integrating digital health technology into the field of medical devices. As the diabetes digital health field continues to develop and become more fully integrated into everyday life, we wish to ensure that it is based on the best evidence for safety and efficacy. As a result, we bring to light several issues that the diabetes community, including regulatory authorities, policymakers, professional organisations, researchers, people with diabetes and healthcare professionals, needs to address to ensure that diabetes health technology can meet its full potential. These issues range from inadequate evidence on app accuracy and clinical validity to lack of training provision, poor interoperability and standardisation, and insufficient data security. We conclude with a series of recommended actions to resolve some of these shortcomings.

Acide hyaluronique intra articulaire dans la gonarthrose: une étude long-terme, ouverte, de Phase IV, avec analyse détaillée par stade de Kellgren-Lawrence.

INTRODUCTION: Les injections intra articulaires (IA) d'acide hyaluronique (HA) désignées sous le nom de viscosupplémentation (VS), sont fréquemment utilisées dans le traitement symptomatique de la gonarthrose (OA), une affection ostéo-articulaire chronique douloureuse et handicapante, qui touche une fraction importante de la population âgée. La sévérité de la gonarthrose est en général décrite par la classification en stades radiologiques de Kellgren-Lawrence (KL). La VS a été largement étudiée à travers de nombreux essais cliniques; cependant, les résultats sont rarement analysés en détail, en fonction du stade KL. MÉTHODE: Une étude ouverte importante, portant sur 1 177 patients souffrant de gonarthrose, fut réalisée de 2004 à 2007. Chaque patient a reçu un traitement de VS consistant en 3 injections d'ARTHRUM H 2% (LCA Pharmaceutical, Chartres, France). A l'inclusion, les patients ont été décrits par leur profil démographique, leur indice de masse corporelle (IMC), leur stade KL et leur état clinique selon les sous-scores douleur et fonction de l'indice Western Ontario and McMaster Universities (WOMAC). Les visites de suivi étaient à M3, M6 et M9 (mois) après la VS. Cette large base de données a été entièrement retraitée en 2019, de manière à fournir une analyse séparée par stade KL, et fut complétée par l'évaluation des taux de patients répondeurs (%) au traitement, selon l'Outcome Measures in Rheumatoid Arthritis Clinical Trials & Osteoarthritis Research Society International (OMERACT-OARSI). L'analyse fut menée à la fois sur les populations en intention de traiter (ITT) et per protocole (PP) ayant terminé l'étude. RÉSULTATS: En analyse ITT du critère principal, les variations du sous-score WOMAC A (douleur) depuis l'inclusion jusqu'à la fin de l'étude, ont été respectivement de 19,8 ; 19,8 ; 17,8 et 14,2, sur une échelle de 0-100, pour les patients des stades KL I à KL IV. En analyse PP dans les mêmes conditions, ces variations ont été de 20,6 ; 19,9 ; 17,1 et 11,7. Tous ces résultats étaient significatifs par rapport aux valeurs à l'inclusion (p<0.001) et cliniquement pertinents à chaque stade KL. Des améliorations significatives ont été également observées pour le sous-score WOMAC C (fonction), et pour les autres critères secondaires. Le taux de répondeurs OMERACT-OARSI variait de 72 à 82% pour les patients KL I à III à M6 et M9. Pour les patients KL IV, le maximum atteint a été 47.7% à M6. Les autres paramètres tels que le sexe, l'IMC ou l'âge, ne furent pas identifiés comme des facteurs de pronostic pour la réponse à la VS. CONCLUSIONS: L'analyse détaillée par stade KL d'une large cohorte de patients suivis en ouvert, suggère le traitement de VS avec ARTHRUM H 2% est applicable à une grande variété de patients gonarthrosiques.

Navigating Medical Device Certification: A Qualitative Exploration of Barriers and Enablers Amongst Innovators, Notified Bodies and Other Stakeholders.

BACKGROUND: Medical device certification has undergone significant changes in recent years. However, exploration of stakeholder experiences remains relatively limited, particularly in the context of software as a medical device. This study sought to explore stakeholder experiences of medical device certification across both the UK and EU. METHODS: Semi-structured interviews (n = 22) analysed using inductive-thematic analysis, synthesised using activity theory. RESULTS: Innovators, consultants and notified bodies share more similarities than differences when discussing barriers and enablers to achieving medical device certification. Systemic tensions between existing rules, tools, community understanding and division of labour currently undermine the intended aim of certification processes. Existing rules are considered complex, with small and medium-sized enterprises considered disproportionality affected, resulting in several unintended outcomes including the perceived 'killing' of innovation. Existing certification processes are described as unfit for purpose, unethical and unsustainable. CONCLUSION: Stakeholder experiences suggest that the intention of establishing a robust and sustainable regulatory framework capable of ensuring a high level of safety whilst also supporting innovation is not yet being realised. Failure to enact desired changes may further jeopardise future innovations, outcomes and care quality.

Vulnerability management as compliance requirement in product security regulation-a game changer for producers' liability and consequential improvement of the level of security in the Internet of Things?

The article outlines the European Union (EU) regulation of information technology (IT) security in Internet of Things products from a consumer and end user perspective. It starts with civil law and the necessity to address security requirements and specifications in individual contractual terms. Data and consumer protection laws have not helped much, mainly because of missing definitions and levels of applicable security. Two new EU directives reforming the law of obligations may improve the situation for consumers since security is now a named quality requirement, especially for the sale of (digital) goods. Also introduced is the provision of security updates as a contractual duty. But both rule sets address only the traders, not the producers. This is different with the activation of clauses in the radio equipment directive, which sets IT security measures as requirements to be compliant for CE labeling. An important element is the introduction of a vulnerability management system. Details can be found in the draft of technical standard ETSI/EN 303645. The work concludes with a look at the EU's efforts regarding certification schemes and the interaction of all regulation elements, with more liability for insecure products plus the hope for effectiveness.

Artificial Intelligence-Based Software with CE Mark for Chest X-ray Interpretation: Opportunities and Challenges.

Chest X-ray (CXR) is the most important technique for performing chest imaging, despite its well-known limitations in terms of scope and sensitivity. These intrinsic limitations of CXR have prompted the development of several artificial intelligence (AI)-based software packages dedicated to CXR interpretation. The online database "AI for radiology" was queried to identify CE-marked AI-based software available for CXR interpretation. The returned studies were divided according to the targeted disease. AI-powered computer-aided detection software is already widely adopted in screening and triage for pulmonary tuberculosis, especially in countries with few resources and suffering from high a burden of this disease. AI-based software has also been demonstrated to be valuable for the detection of lung nodules detection, automated flagging of positive cases, and post-processing through the development of digital bone suppression software able to produce digital bone suppressed images. Finally, the majority of available CE-marked software packages for CXR are designed to recognize several findings, with potential differences in sensitivity and specificity for each of the recognized findings.

Opportunities and Risks of UK Medical Device Reform.

OBJECTIVES: To identify the potential opportunities and risks around future UK regulatory reform of medical devices. DESIGN: A mixed methods approach, comprising a rapid literature review, one-to-one, semi-structured interviews with key stakeholders, a multidisciplinary stakeholder workshop, and a post-workshop survey. SETTING: United Kingdom. PARTICIPANTS: 32 key stakeholders across the medical device sector were identified both from the public and private sectors. RESULTS: Opportunities relating to regulatory independence were identified, including the potential to create and implement a regulatory framework that ensures availability of medical devices; innovation and investment potential; and safety to the citizens of the UK. The most significant risks identified included threats to the safety of individual patients and the wider health system arising from the delay in awaiting regulatory approval due to the shortage of approved bodies; and reduced competitiveness of UK market and device manufacturers. Recommendations were identified to mitigate risks, centred on harnessing broader cross-sector collaborations, promoting patient and public partnership, and maximizing international engagement. CONCLUSIONS: The UK's medical device sector is at a time-critical juncture to construct a regulatory framework to navigate its exit of Europe and respond to Europe's transition to new medical device regulations whilst also addressing the ongoing demand for rapid approval for new devices in response to the global pandemic. Investment, capacity-building, and international engagement will play a central role in mitigating risks and maximizing opportunities for medical device regulation.

The impact and surgeon perceptions of the suspension of the CE certification of MAGEC devices on clinical practice.

MAGnetic Expansion Control (MAGEC) rods are used in the surgical treatment of children with early onset scoliosis. The magnetically controlled lengthening mechanism enables rod distractions without the need for repeated invasive surgery. The CE certification of these devices was suspended in March 2021 due, primarily, to performance evidence gaps in the documents provided by the manufacturer to regulators and notified bodies. MAGEC rods are therefore not permitted for use in countries requiring CE marking. This was a survey of 18 MAGEC rod surgeons in the UK about their perception of the impact of the CE suspension on the clinical management of their patients. Unsurprisingly, virtually all perceived a negative impact, reflecting the complexity of this patient group. Reassuringly, these surgeons are highly experienced in alternative treatment methods. Cite this article: Bone Jt Open 2022;3(2):155-157.

Drug-eluting bioresorbable scaffolds in cardiovascular disease, peripheral artery and gastrointestinal fields: a clinical update.

INTRODUCTION: The technology of bioresorbable scaffold (BRS) spread out after the success of the first-in-man trials of the Absorb. However, the randomized trials demonstrated that major adverse cardiac events and scaffold thrombosis rates of the first-generation Absorb were higher than those of the metallic everolimus-eluting stent. To overcome the shortcoming of the firstly commercialized Absorb, novel technologies have been developed. AREAS COVERED: In this review, we overviewed the field of BRS in the treatment of coronary, peripheral artery and gastrointestinal fields. To date, 10 BRS devices developed by 6 manufacturers have acquired the CE mark in coronary artery disease. Currently 8 BRS are in clinical trial phase, whereas 7 BRS are in preclinical assessment phase. Most new-generation devices have a strut thickness of less than 100 µm. However, late favorable outcome might be achieved not only by device refinement but also by a proper technique of implantation using intra vascular imaging guidance, as well as with a careful patient and lesion selection. EXPERT OPINION: New-generation BRS will be soon tested in the clinical arena to demonstrate improved acute and long-term of safety and efficacy.

Medical devices in allergy practice.

Medical devices provide people with some health benefits in terms of diagnosis, prevention, treatment, and monitoring of disease processes. Different medical specialties use varieties of medical devices more or less specific for them. Allergology is an interdisciplinary field of medical science and teaches that allergic reactions are of systemic nature but can express themselves at the level of different organs across the life cycle of an individual. Subsequently, medical devices used in allergology could be regarded as: 1) general, servicing the integral diagnostic and management principles and features of allergology, and 2) organ specific, which are shared by organ specific disciplines like pulmonology, otorhinolaryngology, dermatology, and others. The present position paper of the World Allergy Organization (WAO) is meant to be the first integral document providing structured information on medical devices in allergology used in daily routine but also needed for sophisticated diagnostic purposes and modern disease management. It is supposed to contribute to the transformation of the health care system into integrated care pathways for interrelated comorbidities.

New European Regulation for Medical Devices: What Is Changing?

INTRODUCTION: The Medical Devices Regulation (MDR) 2017/745/EU will fully apply from May 2020. Interventional radiologists use medical devices on a daily basis and so must be aware of the impact that this new regulation will have on their daily practice. MATERIALS AND METHODS: In this paper, we describe the major transformation that the MDR brings to the medical devices sector, with a focus on clinical evaluations and clinical investigations. RESULTS: This regulation significantly tightens controls to ensure that devices are safe and effective. In addition, equivalence to already existing devices, which allowed an accelerated access to the market, will now be possible only in some cases. Furthermore, post-marketing clinical follow-up is extended under the MDR and is required for all devices. These new requirements will probably lead to a dramatic increase in the number of clinical investigations and also to a delay in the availability of certain devices on the market. CONCLUSIONS: In the coming years, interventional radiologists are likely to be affected by these changes in their daily practice, in terms of medical device availability and/or in terms of increased involvement in clinical investigations.

FDA, CE mark or something else?-Thinking fast and slow.

There is a robust debate going on among the Medical Device stake-holders whether FDA is better or CE mark or something else. Currently process of obtaining an FDA approval is bogged down by ever-increasing unpredictability, inconsistency, prolonged time, and huge expense but CE mark has its own problems. Historically, the Japanese review process has tended to be the slowest among the big three but recently with the introduction of accelerated review process there has been a significant progress. While the goal of an innovator/manufacturer is to develop, manufacture and market a medical device that addresses an unmet clinical need, the requisite regulatory approval process can be very confusing. Not only there is a whole lot of jargon tossed around by regulatory affair professionals: "substantial equivalence," "PMDA," "CE mark," "Notified body," "510K" and "PMA" but the actual approval process can also be very tardy, inconsistent and expensive.

The new EU regulation on in vitro diagnostics: potential issues at the interface of medicines and companion diagnostics.

The new European regulation for in vitro diagnostics (IVD) divides the certification of IVD including companion diagnostics (CDx) by notified bodies (NB) from the market authorization of medicines. With the new regulation, CDx will require conformity assessment which is expected to include clinical evidence by NB. This is a significant change from the current situation: until now most IVD have been certified based on their manufacturers' assessment. For one medicine assessed by the EMA, certification of several different CDx by different NB is possible. As the benefit-risk balance of the medicine may depend on the performance (e.g., sensitivity and specificity) of its CDx, a close cooperation of EMA and NB will be necessary. The availability of detailed information on CDx used in the pivotal clinical trials for the medicine's authorization will become crucial for the assessment of alternative or competing CDx.

Barriers to medical device innovation.

The US Food and Drug Administration (FDA) has defined a medical device as a health care product that does not achieve it's purpose by chemical action or by being metabolized. This means that a vast number of products are considered medical devices. Such devices play an essential role in the practice of medicine. The FDA classifies medical devices in three classes, depending on the risk of the device. Since Class I and II devices have relatively simple requirements for getting to the market, this review will focus on "implantable devices", which, in general, belong to Class III. The European Union and Canada use a slightly different classification system. While early generations of medical devices were introduced without much testing, either technical or clinical, the process of introducing a Class III medical device from concept to clinical practice has become strongly regulated and requires extensive technological and clinical testing. The modern era of implantable medical devices may be considered to have started in the 1920s with development of artificial hips. The implantable pacemaker was another milestone and pacemakers and cardioverters/defibrillators have since saved millions of lives and created commercial giants in the medical device industry. This review will include some examples of cardiovascular devices. Similar considerations apply to the total implantable device market, although clinical and technological applications obviously vary considerably.