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Abstract
Background The evolution of neuroendovascular technologies has progressed substantially. Over the last two decades, the introduction of new endovascular devices has facilitated treatment for more patients, and as a result, the regulatory environment concerning neuroendovascular devices has evolved rapidly in response.
Objective To examine trends in the approval of neuroendovascular devices by the United States Food and Drug Administration (FDA) over the last 20 years.
Methods Open-access US FDA databases were queried between January 2000 and December 2022 for all devices approved by the Neurological Devices Advisory Committee. Neuroendovascular devices were manually classified and grouped by category. Device approval data, including approval times, approval pathway, and presence of predicate devices, were examined.
Results A total of 3186 neurological devices were approved via various US FDA pathways during the study period. 320 (10.0%) corresponded to neuroendovascular devices, of which 301 (94.1%) were approved via the 510(k) pathway. The percentage of 510(k) pathway neuroendovascular devices increased from 6.9% to 14.3% of all neuro devices before and after 2015, respectively. There was an increase in approval times for neuroendovascular devices cleared after 2015.
Conclusion Over the last two decades, the neuroendovascular device armamentarium has rapidly expanded, especially after positive stroke trials in 2015. Regulatory approval times are significantly affected by device category, generation, company size, and company location, and a vast majority are approved by the 510(k) pathway. These results can guide further innovation in the endovascular device space and may act as a roadmap for future regulatory planning.
- Device
- Technology
Data availability statement
Data are available upon reasonable request. Not applicable.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Over the past few decades, there has been a significant increase in the number of endovascular devices, the range of their indications, and the complexity of technology.
WHAT THIS STUDY ADDS
Our study is the first to quantify FDA approvals over the past two decades. We have identified important factors affecting regulatory approval time for endovascular devices and identified a large increase in the number of endovascular devices approved after 2015.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
Analyzing regulatory trends can help foster innovation in the field and guide clinicians and innovators on how to advance the field.
Introduction
Over the last several decades, the treatment of neurological disease has dramatically shifted with the development of novel endovascular techniques and devices. The emergence of neuroendovascular treatment paradigms has facilitated a safe and effective minimally invasive treatment of ischemic stroke and intracranial aneurysms. Patients with ischemic stroke due to large vessel occlusion have benefitted from technological developments in stent retrievers, aspiration catheters, and intracranial access catheters, whereas patients with intracranial aneurysms can now be treated with flow-diverting stents, intravascular devices, and other innovations to increase safety and aneurysm occlusion rates.1–3
Technological advancement in the United States hinges on the approval of new devices by the Food and Drug Administration (FDA). The degree to which a new device is regulated is based on an assessment of risk to patients.4 Each device is classified as either class I, class II, or class III, which denote an increasing degree of risk.5 The process of approval for each class of device varies. Premarket approval (PMA) is required for high-risk, class III devices without a substantially equivalent predicate device, and typically requires non-clinical and clinical data. The premarket notification (PMN; 510(k)) pathway for class II devices is less stringent, without the need for clinical testing, but the device must be proved to be substantially equivalent to an FDA-approved predecessor device.6 Other less frequent approval processes are the de novo pathway (similar to PMA, but for less risky class II devices without a predicate device) or the humanitarian device exemption (HDE) pathway, which is intended for devices that will benefit patients with rare conditions.
Given the rapid advancement of device development and clinical applications in neuroendovascular surgery over the past two decades, we examined trends in the approval of these devices, based on publicly available FDA databases. We hypothesize that device approval shifted to endovascular devices used in stroke compared with other indications (such as aneurysm embolization) after the publication of positive clinical trials in 2015 and have continued to dominate the regulatory landscape over the last 5 years.
Methods
United States FDA open access, publicly available databases were queried for all medical devices approved by a variety of regulatory pathways, including 510(k) PMN,7 PMA,8 de novo,9 and HDE.10 The comprehensive database for each regulatory pathway was queried between January 1, 2000 and December 31, 2022. Regulatory filings were sorted by the date received by the FDA as well as the date approval was gained; approval time was calculated as the difference between these dates. Medical devices were sorted by reviewing advisory committee, and only those reviewed by the Neurological Devices Advisory Committee were included for subsequent analysis. Each device within each regulatory pathway was manually reviewed by two study authors (JR and KY) for its indications for use in endovascular neurosurgery. Devices were further broken down by intended use: devices were separated into the broad categories of embolic devices (coils, liquid embolic agents), microguidewires, microcatheters, intracranial access catheters, aspiration catheter systems, and stent retrievers. Devices approved by the 510(k) pathway were also dichotomized depending on whether they were a first-generation device or if they were a subsequent iteration of a previously approved device. This was performed by manually reviewing the FDA documentation and determining the device’s predicate. If the predicate was a previously approved version of a device in the same company’s portfolio, it was labeled as ‘subsequent generation.’ If the device predicate had been previously approved by a different company, it was labeled as ‘first generation.’ Lastly, medical device company information was recorded, including country of origin and financial status (whether it had been acquired since device approval, publicly traded, or privately owned).
Statistical analysis
Statistics were completed using IBM SPSS Statistics (version 28.0). Relationship between category of device, presence of a predicate device, country of origin, financial status, and number of total devices from each company (binary group as either ≥5 devices or<5 devices) compared with average approval time was determined using Student t-tests and analysis of variance (ANOVA) as appropriate. Values are represented as mean±SD or number (%).
Results
Neuroendovascular devices
Over the 22-year period between January 1, 2000 and December 31, 2022, a total of 320 endovascular devices were approved or cleared for use by the FDA Neurological Devices Advisory Committee, including 301 PMN, 8 PMA, 2 DEN, and 9 HDE. Of all devices approved by the committee (3186 total) during this time frame, endovascular devices made up 9.7% of all 510(k), 22.2% of all PMA, 5.4% of all DEN, and 69.2% of all HDE clearances (online supplemental table 1). Mean approval times for endovascular devices depended on the regulatory pathway: 105.9±89.1 days for 510(k), 452.9±179.7 days for PMA, 442.5±184.6 days for DEN, and 310.6±93.4 days for HDE (P<0.01).
Supplemental material
510(k) pathway devices
Given the relative infrequency of neuroendovascular device approval by the PMA, DEN, and HDE pathways, further quantitative analysis was performed on the cohort of 510(k) cleared devices. Between 2000 and 2022, the annual number of Neurological Devices Advisory Committee 510(k) clearances ranged from 79 devices in 2010 to 172 in 2001 and 2017 with a mean of 134.8±27.4 devices (figure 1). The proportion of endovascular-specific devices has trended up over this period, with a major spike seen after 2015. The average annual percentage of endovascular devices was 6.9±3.4 before 2015 and 14.3±5.6 after 2015 (inclusive) (P<0.01).
All 510(k) pathway device approvals by the Neurological Devices Advisory Committee between 2000 and 2022. The trend line represents the percent of approved endovascular devices relative to the total number of all neuro devices approved by the committee.
There has been an upward trend in regulatory clearance by the 510(k) pathway for neuroendovascular devices between 2000 and 2022, with a peak of 33 devices approved in 2019 and 2021 (figure 2). During this period, approvals for embolic devices (coils, particles, etc) have trended down, whereas devices used in endovascular thrombectomy (stent retrievers, aspiration systems, and intracranial access catheters) have risen substantially, especially over the last 5 years. This increase in devices for stroke and intracranial access has driven the overall increase in neuro device 510(k) clearances since 2015.
Number of endovascular devices approved by category, including aspiration systems (AS), microwires (MW), microcatheters (MC), intracranial access and balloon guides (IA+BG), coils/liquid embolics (C/L EMBO), and stent retrievers (SR).
Device approval times
While the mean approval time for all 510(k) endovascular device clearances was 105.9 days during the study period, the annual median approval time ranged from 23 days in 2000 to 189 days in 2001 (figure 3). There has been an increase in approval times between the average approval time before 2015 (80.7±72.3 days) and after 2015 (inclusive) (123.7±95.6 days, P<0.01). When assessing device approval times depending on intended uses, implanted embolic devices such as coils and liquid embolic agents were excluded to better assess non-implantable endovascular devices only. Overall approval times ranged from 179.4±141.7 days for microcatheters to 73.0±61.2 days for microguidewires (table 1)). First-generation devices (for which the predicate device had been cleared by a different company) had an approval time significantly longer than subsequent-generation devices that were based on a previously FDA-cleared model (176.0±108.9 days vs 107.5±87.9 days, P<0.01 (table 1)).
Median approval time for all endovascular devices.
Approval time for 510(k) pathway devices excluding embolic agents
Industry representation
Overall, 31 companies, representing six countries had device clearances excluding embolic agents over the study period. US-based companies (85.5%) had shorter mean approval time than foreign entities (118.7±90.4 days compared with 173.8±128.4 days, respectively, P=0.01). Lastly, companies that had five or more device clearances had a shorter time to approval than smaller companies with fewer than five device clearances (113.6±91.3 vs 174.7±109.1 days, P<0.01). Of note, company ownership status (publicly traded, privately owned, or bought by or merged with another company) had no effect on the time to approval.
Discussion
This comprehensive analysis has demonstrated the changing landscape in neuroendovascular device approval by the FDA Neurological Advisory Committee between 2000 and 2022. To date, few other therapeutic interventions have proved to be as effective as thrombectomy in improving functional outcomes.11 Thus, there has been substantial innovation by both academia and industry in designing devices to improve intracranial access, recanalization rates, and clinical outcomes. The number of regulatory approvals for neuroendovascular devices has increased since the five positive thrombectomy trials published in 2015 (figure 1). Furthermore, the increasing proportion of devices used in thrombectomy (from 6.9% of all neuro devices to 14% before and after 2015, respectively) has accounted for this overall increase in neuroendovascular device approval. A secondary postulated motivation for endovascular stroke device development would be to financially capitalize on the growing market, which is supported by the growing number of startup companies entering the space with new FDA approvals in the last 8 years.
Neuroendovascular devices approved with the use of a substantially equivalent device from the same company were approved more quickly than devices without an earlier generation predicate (108 vs 176 days, respectively) since the presence of a predicate device with similar technical characteristics may require less scrutiny than a first-generation device. Along similar lines, regulatory scrutiny on US-based companies may be less than for foreign companies, which can explain the shorter approval times between the two groups (119 vs 174 days, respectively). Furthermore, the shorter approval times for larger companies (with ≥5 devices approved) compared with smaller companies (114 days vs 175 days, respectively) may be due to larger companies having existing relationships with FDA regulators or a greater budget for regulatory consulting. Ultimately, these shortened times may also represent improved domestic corporate infrastructure in dealings with the FDA.
The FDA has a stated goal of 90 calendar days between regulatory submission to the determination of substantial equivalence for a 510(k) filing.12 Our findings indicate that before 2015, the average approval time was nearly 81 days, whereas, after 2015 (inclusive), the approval times significantly increased to 124 days. The results of the 2015 clinical trials generated significant industry interest in the space, resulting in the number of FDA approvals and time to approval increasing.
The FDA 510(k) approval process is limited to moderate risk (class II) devices with a predicate device.6 Given the risk profile of devices used in neurointerventional surgery, nearly all devices (94%) in the time frame were approved by the 510(k) premarket notification process. Of the remaining 6%, most were implanted devices, approved by either the PMA, HDE, or DEN pathways. These include intracranial stents, flow-diverting stents, intravascular devices, and liquid embolic agents. Of these devices, only two were not intended for permanent implantation: the NeVa VS device (Vesalio, Nashville, USA) and the modified Trevo ProVue stent retriever (approved under Concentric Medical, acquired by Stryker Neurovascular, Salt Lake City, USA).
Based on these results, there is regulatory momentum to approve devices for the use of endovascular thrombectomy. A vast majority of endovascular devices used in the treatment of large vessel occlusion have been approved by the 510(k) pathway, probably owing to their simplicity in design, safety in clinical use, and the proven benefit of the procedure in improving outomes for patients with a stroke. This finding demonstrates the need for high-quality evidence in defining the device market (ie, endovascular thrombectomy after 2015) and highlighting to industry and other innovators the possible impact on investments in novel device research and development. Importantly, these results point to a successful collaboration between clinicians, academia, and industry, which has helped to drive innovation in devices to the benefit of neurosurgical patients.
Limitations
This study is a comprehensive historical cohort of US FDA neuroendovascular devices approved over the last 22 years. Thus, the results are only applicable to the US market. Moreover, this study is based on open access, publicly available databases and is subject to uncontrolled errors that may be present in those databases beforehand. Furthermore, the total number of regulatory submissions (vs final device approvals) is not publicly available, so any trends in the total number of FDA submissions cannot be determined.
Conclusions
Over the last two decades, increasing numbers of neuroendovascular devices have been approved, with a significant growth of approved devices used in endovascular thrombectomy after 2015, when the first positive randomized controlled trials were published. Most neuroendovascular devices are considered as moderate risk and approved under the 510(k) pathway, and the average time from submission to approval was 106 days for devices approved through this pathway. In a field dependent on technology to improve patient outcomes, it is essential to promote collaboration between healthcare providers, regulators, and industry to allow access to highly effective means of treatment for acute stroke; understanding trends in regulatory approaches can help to facilitate further innovation in this field.
Data availability statement
Data are available upon reasonable request. Not applicable.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
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Contributors LSB, KAY: conceptualization, formal analysis, writing - original draft, writing - review and editing. TH, JR, BDP: conceptualization, writing - review and editing. AH, AHF, GWB: supervision, writing - review and editing. LSB is the guarantor for this work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.