[Monitoring System of Medical Device Adverse Events in the US and Application of MAUDE Database in Medical Device Registration].

In order to achieve precise risk control of medical devices, it is necessary to establish a scientific evaluation system throughout the entire life cycle of medical devices that focuses on risk identification and risk control. This study summarizes the medical device adverse event monitoring system of the US on regulatory agencies and regulatory law, adverse events reporting forms and time limits, adverse event database, adverse event report analysis and evaluation, as well as adverse event feedback and control. Furthermore, some examples are provided to illustrate the application of the MAUDE database in risk analysis, physical and mechanical performance research, and clinical evaluation of medical device registration and application materials.

Lessons on the use of real-world data in medical device research: findings from the National Evaluation System for Health Technology Test-Cases.

Aim: Although the US FDA encourages manufacturers of medical devices to submit real-world evidence (RWE) to support regulatory decisions, the ability of real-world data (RWD) to generate evidence suitable for decision making remains unclear. The 2017 Medical Device User Fee Amendments (MDUFA IV), authorized the National Evaluation System for health Technology Coordinating Center (NESTcc) to conduct pilot projects, or 'Test-Cases', to assess whether current RWD captures the information needed to answer research questions proposed by industry stakeholders. We synthesized key lessons about the challenges conducting research with RWD and the strategies used by research teams to enhance their ability to generate evidence from RWD based on 18 Test-Cases conducted between 2020 and 2022. Materials & methods: We reviewed study protocols and reports from each Test-Case team and conducted 49 semi-structured interviews with representatives of participating organizations. Interview transcripts were coded and thematically analyzed. Results: Challenges that stakeholders encountered in working with RWD included the lack of unique device identifiers, capturing key data elements and their appropriate meaning in structured data, limited reliability of diagnosis and procedure codes in structured data, extracting information from unstructured electronic health record (EHR) data, limited capture of long-term study end points, missing data and data sharing. Successful strategies included using manufacturer and supply chain data, leveraging clinical registries and registry reporting processes to collect and aggregate data, querying standardized EHR data, implementing natural language processing algorithms and using multidisciplinary research teams. Conclusion: The Test-Cases identified numerous challenges working with RWD but also opportunities to address these challenges and improve researchers' ability to use RWD to generate evidence on medical devices.

Pediatric Device Clinical Trials Activity: 1999-2022.

OBJECTIVES: This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. METHODS: The site www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. RESULTS: A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. CONCLUSIONS: Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

Women's Representation in RCTs Evaluating FDA-Supervised Medical Devices: A Systematic Review.

This systematic review evaluates the representation of women in randomized clinical trials (RCTs) of US Food and Drug Administration (FDA)­supervised medical devices.

EU's Medical Device Expert Panels: Analysis of Membership and Published Clinical Evaluation Consultation Procedure (CECP) Results.

BACKGROUND: The new EU Medical Device Regulation (MDR) places greater importance on the role of clinical evidence to establish safety and performance. Article 54 of the MDR calls for expert committees to independently review the scientific, technical, and clinical evidence supporting the market authorization of certain novel devices independently from the established process of Notified Body reviews. These experts provide a review and opinion that ultimately is taken into consideration alongside the information reviewed by the Notified Body during the review process. Four expert committees (General and Plastic Surgery and Dentistry; Orthopaedics, Traumatology, Rehabilitation, Rheumatology; Circulatory System; and Neurology) have published at least one Scientific Opinion (SO) under the Clinical Evaluation Consultation Procedure (CECP) in 2021-2022. METHODS: The four expert committees with published CECP opinions were reviewed to assess the academic backgrounds and professional expertise of each member with respect to clinical, technical, and biological domains on a 0-2 scale for each domain. A content review was conducted on the 10 CECP opinions published by these committees to assess their consistency with the goals and outcome expectations set by the MDR. The extent of content related to each of the clinical, technical, and biological domains was also assessed on a 0-2 scale. RESULTS: All committees were composed primarily by members with strong clinical expertise, but only a few had strong technical and biological expertise. Across committees, the average scores of members related to academic background and professional expertise both ranged from 1.64 to 2.00 in the clinical domain, but only 0-0.15 and 0.15-0.69, respectively, in the biological domain, and 0.12-0.55 and 0.23-0.73, respectively, in the technical domain. A content review for the 10 SOs showed that all opinions focused exclusively or primarily on the clinical evidence. Three contained a modest amount of additional text directed at technical/engineering issues and five at biological issues. CONCLUSION: Expert committees are composed predominantly of expert clinical reviewers but have many fewer members with significant technical or biological expertise. This may limit the ability of the committees to evaluate the significant technical and biological risks that are often best understood by preclinical testing. Broadening the expertise across the committees may improve the depth of their benefit/risk critiques.

The fragility index and reverse fragility index of FDA investigational device exemption trials in spinal fusion surgery: a systematic review.

PURPOSE: FDA investigational device exemption (IDE) studies are considered a gold standard of assessing safety and efficacy of novel devices through RCTs. The fragility index (FI) has emerged as a means to assess robustness of statistically significant study results and inversely, the reverse fragility index (RFI) for non-significant differences. Previous authors have defined results as fragile if loss to follow up is greater than the FI or RFI. The aim of this study was to assess the FI, RFI, and robustness of data supplied by IDE studies in spinal surgery. METHODS: This was a systematic review of the literature. Inclusion criteria included randomized controlled trials with dichotomous outcome measures conducted under IDE guidelines between 2000 and 2023. FI and RFI were calculated through successively changing events to non-events until the outcome changed to non-significance or significance, respectively. The fragility quotient (FQ) and reverse fragility quotient (RFQ) were calculated by dividing the FI and RFI, respectively, by the sample size. RESULTS: Thirty-two studies met inclusion criteria with a total of 40 unique outcome measures; 240 outcomes were analyzed. Twenty-six studies reported 96 statistically significant results. The median FI was 6 (IQR: 3-9.25), and patients lost to follow up was greater than the FI in 99.0% (95/96) of results. The average FQ was 0.027. Thirty studies reported 144 statistically insignificant results and a median RFI of 6 (IQR: 4-8). The average RFQ extrapolated was 0.021, and loss to follow up was greater than the RFI in 98.6% (142/144) of results. CONCLUSIONS: IDE studies in spine surgery are surprisingly fragile given their reputations, large sample sizes, and intent to establish safety in investigational devices. This study found a median FI and RFI of 6. The number of patients lost to follow-up was greater than FIand RFI in 98.8% (237/240) of reported outcomes. FQ and RFQ tell us that changes of two to three patients per hundred can flip the significance of reported outcomes. This is an important reminder of the limitations of RCTs. Analysis of fragility in future studies may help clarify the strength of the relationship between reported data and their conclusions.

What is the MAUDE Database Telling us about 510(k) Authorization? Evaluation of Two Generations of Endovascular Arteriovenous Fistula Devices.

BACKGROUND: In 2019, Bard Peripheral Vascular Inc (BV; now Becton, Dickinson and Company; Sparks, Maryland) received Food and Drug Administration (FDA) approval to begin marketing the WavelinQ EndoAVF System through a process known as 510(k) authorization. Such authorization relies on BV proving that the new WavelinQ EndoAVF System was of "substantial equivalence" to the WavelinQ 4F EndoAVF System. We set forth to analyze patient problems and device issues reported for the new device and determine if they were significantly different from the predicate device its 510(k) approval was based on. METHODS: FDA database Manufacturer and User Facility Device Experience was queried for all adverse report events for the WavelinQ EndoAVF System and WavelinQ 4F EndoAVF System. Data were collected on patient issues and device issues. Fisher's exact test was used. RESULTS: There were a total of 125 reports for the WavelinQ 4F EndoAVF System and 78 for the WavelinQ EndoAVF System. There was a significant increase in patient problem "hypertension" (0% vs. 5.1%; P = 0.02) for the WavelinQ EndoAVF System but a statistically significant decrease in device issue "failure to align" for the WavelinQ EndoAVF System (24.8% vs. 10.3%; P ≤ 0.01). CONCLUSIONS: There were changes in device and patient outcomes between the WavelinQ EndoAVF System and WavelinQ 4F EndoAVF System. While we noted a decrease in device problem "failure to align", there was an overall increase in patients' "hypertension" rates. This highlights the importance of the FDA Manufacturer and User Facility Device Experience reporting in ensuring that device safety is maintained when devices are approved for marketing through the 510(k) process.

Overview of the 2023 FDA Circulatory System Devices Advisory Panel meeting on the Recor Paradise Ultrasound-Based Renal Denervation System.

Hypertension continues to be a prominent, avoidable factor contributing to major vascular issues on a global scale. Even with lifestyle adjustments and more aggressive medical treatments, maintaining optimal blood pressure levels remains challenging. This challenge has driven the emergence of device-oriented approaches to address hypertension. To assess the safety and efficacy of the Recor Paradise Ultrasound Renal Denervation System, the Circulatory System Devices Panel was convened by the US Food and Drug Administration (FDA). This manuscript provides a condensed overview of the information put forth by the sponsor and the FDA, along with an account of the considerations and conversations that took place during the meeting.

Regulatory Framework for Drug-Device Combination Products in the United States, Europe, and Korea.

Combination products (CPs) combine two or more product types such as drugs, devices, and/or biological products for increased safety and clinical effectiveness. The emergence of innovative CPs poses new challenges for regulatory agencies in assigning jurisdiction for premarket review and oversight. In US, the 1990 Safe Medical Devices Act defines and provides classification criteria for CPs, and the US government has developed a regulatory process through multiple acts, including the 21st Century Cures Act of 2016. Meanwhile, regulators in the European Union (EU) and the Republic of Korea have recently recognized the importance of premarket pathways for CPs. The European Medicines Agency (EMA) has issued guidelines and explanations on compliance issues related to drug-device CPs under MDR. EMA doesn't have the definitions of CPs, but uses the term drug-device combination products (drug-device CPs). CPs are categorized as drugs or medical devices, which follow their relevant regulatory framework. The Ministry of Food and Drug Safety (MFDS) in Korea has legal definitions of CPs under the Notice of the MFDS. CPs are designated as drugs or medical devices according to their primary mode of actions (PMOA) and follow regulatory processes through the framework of drugs or medical devices. This study aims to comprehensively summarize the regulatory oversight of CPs by analyzing the regulatory policies and legal frameworks in the US, the EU, and Korea. The regulatory challenges encountered when developing CPs are also discussed. With specific emphasis on the combination of drugs and devices, this study provides in-depth insights into the regulatory landscape, shedding light on the unique challenges associated with the development of CPs for this particular intersection of drugs and devices.

Overview of 2024 FDA Advisory Panel Meeting on the TriClip transcatheter tricuspid valve repair system.

Tricuspid regurgitation (TR) is common and associated with significant mortality and morbidity. Because the effectiveness and safety of medical and surgical treatments are limited, there is a significant unmet need for the treatment of this disease. Therefore, there is a growing market for percutaneous devices that offer safer, less invasive, and more effective treatment options in this patient population. On February 13, 2024, the US Food and Drug Administration (FDA) convened a meeting of the Circulatory System Devices Panel to discuss the safety and effectiveness of the TriClip Transcatheter Valve Repair System (Abbott, Santa Clara, CA, USA). Several important points were discussed, including newly published data from the TRILUMINATE Pivotal study, the use of patient-oriented outcomes for device approval, and a discussion about training requirements and rollout plans when approving a breakthrough device. In this manuscript, we summarize the data presented by the sponsor and FDA and describe the deliberations and discussions during the meeting.

Is read-across for chemicals comparable to medical device equivalence and where to use it for conformity assessment?

Novel medical devices must conform to medical device regulation (MDR) for European market entry. Likewise, chemicals must comply with the Registration, Evaluation, Authorization and Restriction of Chemicals (REACh) regulation. Both pose regulatory challenges for manufacturers, but concordantly provide an approach for transferring data from an already registered device or compound to the one undergoing accreditation. This is called equivalence for medical devices and read-across for chemicals. Although read-across is not explicitly prohibited in the process of medical device accreditation, it is usually not performed due to a lack of guidance and acceptance criteria from the authorities. Nonetheless, a scientifically justified read-across of material-based endpoints, as well as toxicological assessment of chemical aspects, such as extractables and leachables, can prevent failure of MDR device equivalence if data is lacking. Further, read-across, if applied correctly can facilitate the standard MDR conformity assessment. The need for read-across within medical device registration should let authorities to reconsider device accreditation and the formulation of respective guidance documents. Acceptance criteria like in the European Chemicals Agency (ECHA) read-across assessment framework (RAAF) are needed. This can reduce the impact of the MDR and help with keeping high European innovation device rate, beneficial for medical device patients.

The FDA Reclassification of Cervical Pedicle and Lateral Mass Screws: A Case Study in Regulatory History.

The classification of medical devices by the Food and Drug Administration (FDA) involves rigorous scrutiny from specialized panels that designate devices as Class I, II, or III depending on their levels of relative risk to patient health. Posterior rigid pedicle screw systems were first classified by the FDA in 1984 and have since revolutionized the treatment of many spine pathologies. Despite this early classification by the FDA, posterior cervical pedicle and lateral mass screws were not reclassified from unclassified to Class III and then to Class II until 2019, nearly 35 years after their initial classification. This reclassification process involved a decades-long interplay between the FDA, formal panels, manufacturers, academic leaders, practicing physicians, and patients. It was delayed by lawsuits and a paucity of data demonstrating the ability to improve outcomes for cervical spinal pathologies. The off-label use of thoracolumbar pedicle screw rigid fixation systems by early adopters assisted manufacturers and professional organizations in providing the necessary data for the reclassification process. This case study highlights the collaboration between physicians and professional organizations in facilitating FDA reclassification and underscores changes to the current classification process that could avoid the prolonged dichotomy between common medical practice and FDA guidelines.

The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Device regulation and surveillance in vascular care: Challenges and opportunities.

Cardiovascular devices are essential for the treatment of cardiovascular diseases including cerebrovascular, coronary, valvular, congenital, peripheral vascular and arrhythmic diseases. The regulation and surveillance of vascular devices in real-world practice, however, presents challenges during each individual product's life cycle. Four examples illustrate recent challenges and questions regarding safety, appropriate use and efficacy arising from FDA approved devices used in real-world practice. We outline potential pathways wherein providers, regulators and payors could potentially provide high-quality cardiovascular care, identify safety signals, ensure equitable device access, and study potential issues with devices in real-world practice.

Considerations for Use of the MAUDE Database in Otolaryngology-Head & Neck Surgery Research.

The use of the US Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) to analyze adverse events linked to medical devices has grown in recent years. MAUDE facilitates post-market surveillance, contributing to the assessment of device performance and the identification of potential safety concerns. The database is instrumental not only for mandatory reporters such as manufacturers and healthcare facilities but also offers a platform for voluntary submissions from clinicians and patients, thus widening the scope of data collection. While the database offers valuable data, there are important limitations that must be understood in order to encourage appropriate interpretation of findings. This commentary highlights the major advantages and disadvantages of the MAUDE database, as well as describes possible areas for improvement in adverse event reporting.

Integrated Devices: A New Regulatory Pathway to Promote Revolutionary Innovation.

Policy Points Current medical device regulatory frameworks date back half a century and are ill suited for the next generation of medical devices that involve a significant software component. Existing Food and Drug Administration efforts are insufficient because of a lack of statutory authority, whereas international examples offer lessons for improving and harmonizing domestic medical device regulatory policy. A voluntary alternative pathway built upon two-stage review with individual component review followed by holistic review for integrated devices would provide regulators with new tools to address a changing medical device marketplace.