FDA classifies medical devices into one of three classes according to the degree of risk and the level of control necessary to ensure the safety and effectiveness of the device.² The three classes are as follows:

Any device that does not fall under an existing class I, II, or III regulation and is not considered a preamendment device, as previously defined, is automatically classified as class III under section 513(f). This automatic classification occurs without any FDA rulemaking process and regardless of the risk. Device manufacturers can submit a request for a formal device determination or classification from the FDA through a 513(g) request before submitting a marketing application.

General controls are the basic provisions that provide the FDA the means of ensuring the safety and effectiveness of medical devices, and they apply to all medical devices regardless of class. These include provisions related to adulteration, misbranding, device registration and listing, premarket notification, banned devices, records and reports, and Good Manufacturing Practices. The
term special controls refers to the additional controls necessary to provide a reasonable assurance of safety and effectiveness for a specific device type where general controls alone have been determined to be insufficient. Special controls have been established for some class II devices based on device-specific considerations and include adherence to guidance documents, performance standards, postmarket surveillance, patient registries or guidelines, and other appropriate actions as identified by the CDRH.³

As the FDA’s experience and knowledge of a device type increases, a device’s classification can be updated through the reclassification process. Devices may be reclassified through the 513(e) or 513(f) processes if new information is provided demonstrating that a lower classification is sufficient or a higher classification is necessary to ensure safety and effectiveness. The 513(f) process includes de novo submissions for novel medical devices that have a risk profile of a class I or II device. The FDA may initiate or industry may petition to reclassify a device, and a panel meeting can be convened for the FDA to solicit expert feedback.⁴ One example is the FDA proposing the reclassification of bone growth stimulators from class III to class II and convening a panel meeting to elicit feedback in September 2020.⁵

FDA regulatory requirements for medical devices encompass the entire product life cycle, including premarket, postmarket, inspection, compliance, and enforcement. General controls are the fundamental regulatory requirements with which all manufacturers of medical devices distributed in the United States must comply³,⁶ (Table 1).

Class III devices are reviewed through the PMA pathway, which constitutes the most rigorous and stringent device marketing application required by the FDA. PMA is based on valid scientific evidence that demonstrates reasonable assurance of safety and effectiveness with a positive benefit-risk profile. PMA submissions most often require clinical data and a quality system review, and the review may involve FDA inspections and/or a public-facing expert panel vote. The PMA pathway can be significantly longer and more expensive than alternative pathways and may result in additional postmarket commitments for the lifetime of the device, such as reporting, surveillance, or postapproval clinical studies. The review time for a PMA is typically 180 days, with the FDA issuing a request for additional information at the 100-day timepoint. The sponsor (submitter) will have 180 days to respond to this request but can request an extension. For orthopaedic devices, IDE clinical studies are rigorous and often have the following features: two-arm randomized controlled trial; noninferiority study compared with an active control; 1-or 2-year primary end point with mandatory 5-year follow-up; minimal loss to
follow-up (target 85% follow-up or higher); and a composite primary end point that incorporates multiple safety and efficacy measures, all of which must be met patient-wise for a clinical success. Typical components of the composite primary outcome measure include a patient-reported outcome instrument; absence of secondary surgical intervention; absence of neurologic symptoms (clinical worsening); radiographic outcomes; and/or absence of device-related severe adverse events. Including the clinical study activities and regulatory processes, PMA approval typically requires a time commitment of more than 5 years and the requisite capital to run a major clinical trial and conduct regulatory actions over a protracted period. Post-PMA modifications are implemented through various supplements such as panel-track supplement, 180-day supplement, real-time supplement, 30-day notice, special PMA supplement, and annual reports.⁷

An IDE allows a device intended for investigational use to be shipped lawfully across the United States and used in a clinical study to collect safety and effectiveness data. Devices that are deemed to pose significant risk to the patient must have an approved IDE before initiation of the clinical study. Nonsignificant risk devices (defined in 21 CFR 812) do not require an IDE, but must follow abbreviated requirements including labeling, institutional review board approval, informed consent, and monitoring. IDEs are reviewed by the FDA within 30 days, with the review focused on evaluating device safety. For reference, the FDA will provide any comments, referred to as study design considerations, on effectiveness end points and/or the ability of a study to support a future marketing application during the IDE review. Study design considerations should not impede approval of the IDE. Sponsors are not required to submit a PMA or 510(k), register their establishment, or list the device while the device is under investigation. Sponsors of IDEs are also exempt from the Quality System Regulation requirements except for the requirements pertaining to design controls.⁸

A premarket notification (ie, a 510(k) submission) is used to obtain clearance of a class II medical device by demonstrating substantial equivalence to a legally marketed predicate device. The 510(k) devices are required to demonstrate that they are expected to be as safe and as effective as a previously cleared class II device with the same intended use. Class III devices, drugs/biologics, or uncleared/unapproved devices may not serve as predicate devices. The differences in technology between the subject and predicate device should not be so significant that there are new risks presented by the subject device not relevant to the predicate technology. Devices may be found not substantially equivalent to the predicate device if they do not meet one of these high-level criteria or if the performance testing does not demonstrate substantial equivalence. A 510(k) is subject to a 90-day review from the FDA, with the FDA typically issuing an Additional Information Request around the 60-day timepoint, placing the review clock on hold. The sponsor will have an additional 180 days to respond to this request, after which the 90-day review clock is resumed. The 510(k)s are typically considered the lowest barrier to entry in terms of both time and cost compared with other premarket pathways.⁹

The De Novo process is a risk-based classification process designed to allow for the classification of novel medical devices that can reasonably be considered low-medium risk class I or class II, but for which there is no predicate device. This process creates a new classification regulation for the device, after which the device can serve as a predicate for future, similar products through the 510(k) pathway. The De Novo review is twofold and first includes a review of current regulations, predicate devices, and the subject technology to determine whether the device is eligible for this type of submission. Second, the device is reviewed to ensure a reasonable assurance of safety and effectiveness and that the benefits of the technology outweigh the risks. De Novo review clocks are 150 days for the FDA review and may include substantial additional hold time to correct any deficiencies after the first 75 days of review. Although an important pathway, few orthopaedic devices have been granted a De Novo to date, though its use may be increasing.