Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium
Key result
High-risk CV devices lack sufficient clinical evidence, with no randomized trials published before CE approval.
- n=97,886
Why the study?
EU Medical Device Regulation 2017/745 challenges stakeholders to ensure transparent, rigorous clinical evaluation, motivating a systematic evaluation of evidence underlying high-risk cardiovascular devices before and after CE-marking.
Key Points
- To systematically evaluate the quality, transparency, and timing of published prospective clinical trial evidence supporting high-risk cardiovascular medical devices before and after European market access (CE-marking) between 2000 and 2021.
- Searched literature published between 2000 and 2021 for prospective clinical studies evaluating 71 high-risk cardiovascular devices across 7 device classes.
- Assessed study design, sample size, protocol registration, outcome adjudication, and adverse event reporting relative to the timing of CE-mark approval.
- Identified 473 reports of 308 prospective studies (N=97,886), comprising 81% non-randomized trials (251/308, n=66,186) and 19% randomized clinical trials (57/308, n=31,700).
- No randomized clinical trial was published prior to CE-mark approval for any evaluated device, and 89% (224/251) of non-randomized trials were published post-approval.
- Pre-approval studies had significantly smaller median sample sizes than post-approval studies (31 vs. 135 individuals, P < .001), while only 49% of all studies pre-registered protocols and 39% reported outcome adjudication.
Study Design
Type
Systematic Review (n=97,886)
Structured PICO
P
Population
308 prospectively designed studies enrolling 97,886 individuals evaluating 71 high-risk cardiovascular devices in seven classes between 2000 and 2021.
I
Intervention
High-risk cardiovascular medical devices (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)
O
Outcome
Quantity and quality of published clinical evidence before and after CE-mark approval
There is a significant lack of high-quality, randomized clinical trial data published prior to CE-mark approval for high-risk cardiovascular devices in the European Union.
Limitations
- The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Larger and better-designed clinical trials of high-risk devices need to be conducted and reported more quickly. More specific EU guidance on clinical trial methodologies, appropriate endpoints, comparators, and follow-up is required, and systems need to be developed to demonstrate concordance of regulatory judgements between Notified Bodies.”
“It is impossible to practise evidence-based medicine unless all results from clinical trials are publicly available. Every patient needs reassurance that any recommendation from their doctor that a medical device should be implanted, will be based on sound evidence. Publication and transparency are essential to establish trust between the patient and doctor.”
“RCTs should be prioritized, conducted, and published efficiently, to prevent delays in effective devices from being broadly used or in harmful ones from being withdrawn from clinical practice. Clinical trials should be appropriately designed to cover all steps in the translation pathway of development and approval for clinical use of high-risk medical devices, without compromise under the pressure of innovation.”
Implication
Many high-risk CV devices enter market with limited RCT evidence; leaves open need for stricter pre- and post-market transparency standards.
Abstract
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.
Discussion
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Cite This Study
Siontis et al. (2023) conducted a systematic review in High-risk cardiovascular medical devices (n=97,886). High-risk cardiovascular medical devices was evaluated on Quantity and quality of publicly available data from prospective clinical investigations before and after CE approval. A systematic review of 308 prospective studies (97,886 individuals) found insufficient clinical evidence for high-risk cardiovascular devices, with no randomized trials published before CE approval.