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In 1997, US Congress established the US Food and Drug Administration (FDA) De Novo premarket review pathway for novel low-risk and moderate-risk medical devices.¹ In recent years, the FDA and medical device manufacturers have increasingly used the De Novo pathway; the FDA cleared 65 devices via this pathway between 1997 and 2012 and an additional 187 between 2013 and 2019.^2-4 Devices cleared through the De Novo pathway represent novel technologies, and approval may serve as the basis for subsequent clearance of devices through the 510(k) pathway.⁵ The 510(k) pathway requires manufacturers to demonstrate that new devices are 鈥渟ubstantially鈥� equivalent to previously cleared devices, typically without clinical studies demonstrating safety or effectiveness. This study characterizes the premarket clinical evidence supporting clearance of moderate-risk therapeutic devices cleared through the De Novo pathway and postmarket experience, including FDA-required postmarket studies, recalls, and subsequent 510(k) clearances.

In conducting this cross-sectional study, we identified moderate-risk therapeutic devices cleared through the De Novo pathway by the FDA between January 1, 2011, and December 31, 2019, using the FDA De Novo database and FDA-designated product codes.⁴ There were 65 moderate-risk therapeutic devices that met these criteria between 2011 and 2019 (eTable in the Supplement). Using previously described methods,⁶ we reviewed publicly available FDA decision summary documents to identify and characterize all pivotal clinical studies鈥攚hich generally serve as the primary basis for device clearance鈥攁nd their primary effectiveness end points.

We searched the FDA鈥檚 522 Postmarket Surveillance Studies and FDA Medical Device Recall databases for each device to identify FDA-required postmarket studies and device recalls, respectively, as of March 22, 2020. To identify subsequently cleared models and competitor products for each device, we searched the FDA 510(k) database on March 13, 2020, using product codes and recorded (as applicable) the dates of (1) the first 510(k) clearance by the device manufacturer after De Novo clearance and (2) clearance by a competing manufacturer.

All information was summarized using descriptive statistics using Microsoft Excel, version 16.40. This study analyzed information made publicly available through FDA databases and therefore did not require institutional review board approval.

Of the 65 moderate-risk therapeutic devices cleared by the FDA via the De Novo pathway between 2011 and 2019, 63 (97%) had publicly available decision summaries. Of these 63 devices, 10 (16%) were implantable and none was life sustaining (Table 1). For 51 devices (81%), FDA clearance was based on 54 pivotal clinical studies; 12 (19%) were not evaluated through pivotal studies. The median number of patients enrolled in pivotal studies was 112.5 (interquartile range [IQR], 73.5-187.0). Nearly half (23; 43%) were blinded, and a majority used randomization (57%) and an active (26%) or sham (35%) comparator. Of 60 studies measuring premarket effectiveness, 36 (60%) had clinical outcomes as primary effectiveness end points (Table 2). However, 17 studies (31%) failed to meet at least 1 primary effectiveness end point.

Only 1 device, a powered exoskeleton to assist ambulation, was subject to an FDA-required postmarket study. None underwent class I (high-risk) recalls. Of the 63 devices, 32 (51%) served as the basis for devices subsequently cleared through the 510(k) process (median days to first clearance: 202 [IQR, 159.0-302.0]), including 16 (25%) serving as the basis for competitor devices (median days to first clearance: 364 [IQR, 184.5-632.0]).

Between 2011 and 2019, the FDA cleared most novel moderate-risk therapeutic devices via the De Novo pathway based on pivotal clinical studies. However, approximately one-fifth of devices were cleared without pivotal clinical studies, and approximately one-third were based on pivotal studies that failed to meet at least 1 primary effectiveness end point. Nevertheless, the FDA rarely required postmarket studies, and devices cleared through the De Novo pathway often served as the basis for new models and competitor products subsequently cleared via the 510(k) process.

Limitations to the present study include that it was restricted to therapeutic devices and is not generalizable to diagnostic devices. This study did not examine non鈥揊DA-required postmarket studies and may therefore underestimate the strength of evidence supporting device safety and effectiveness.

To ensure that better evidence is generated to guide clinical decision-making, the FDA could require that devices cleared through the De Novo pathway meet prespecified effectiveness end points for clearance and that postmarket studies include larger patient populations. Such studies could be particularly informative for devices cleared without pivotal studies and those that failed to meet effectiveness end points.

Accepted for Publication: June 6, 2020.

Corresponding Author: Vinay K. Rathi, MD, MBA, Department of Otolaryngology鈥揌ead and Neck Surgery, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (vinay_rathi@meei.harvard.edu).

Published Online: October 12, 2020. doi:10.1001/jamainternmed.2020.3214

Author Contributions: Mr Johnston had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Johnston, Ross, Rathi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Johnston, Rathi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Johnston.

Supervision: Ross, Rathi.

Conflicts of Interest Disclosures: Mr Johnston reported grants from the US Food and Drug Administration (FDA) through the Yale鈥揗ayo Clinic Center for Excellence in Regulatory Science and Innovation program outside the submitted work. Dr Dhruva reported travel reimbursement from the FDA, the Center for Drug Research and Evaluation/Office of Medical Policy, and the National Evaluation System for Health Technology Coordinating Center, and research grant funding from the Greenwall Foundation and the National Institutes of Health outside the submitted work. Dr Ross reported grants from the FDA, Johnson and Johnson, Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, the National Institutes of Health/National Heart, Lung, and Blood Institute, the Laura and John Arnold Foundation, the Centers for Medicare & Medicaid Services, Medtronic, and the Blue Cross Blue Shield Association outside the submitted work. No other disclosures were reported.