FDA approval and regulation of medical devices: a primer

Clarivate Analytics has added medical device considerations to our coverage of Food and Drug Administration (FDA) advisory committee meetings, publishing the first AdComm Bulletin for medical devices in February 2017. This article gives an overview of medical device classification in the U.S. and of the regulations governing the FDA’s review of application to market medical devices.

Defining “Device”

The Federal Food, Drug, and Cosmetic Act (FD&C Act) presents a detailed definition of “device.” Put succinctly, the term refers to “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory” that is 1) recognized in the National Formulary or the US Pharmacopoeia, 2) intended to help diagnose, cure, ease, treat, or prevent a disease or condition, or 3) intended to affect bodily function or structure—but not by metabolism or chemical action within or on the body.

The term applies to a broad range of healthcare-related items. As explained in the FDA’s 2006 information sheet guidance Frequently Asked Questions about Medical Devices, that list includes surgical lasers, wheelchairs, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. It also extends to tampons, catheters, and breast implants, and to epidural needles, cardiopulmonary blood pumps, cochlear implants, and implantable prostheses, as noted in another of the FDA’s guidances, Significant Risk and Nonsignificant Risk Medical Device Studies. The rules regulating a particular device depend on whether the FDA classifies it as Class I, II, or III.

Device classes

The FDA classifies medical devices based on their intended uses and the level of risk that use poses. Title 21 of the Code of Federal Regulations Part 860 (21 CFR Part 860) contains the provisions pertaining to medical device classification:

Class I devices pose the least risk and are subject only to the baseline, “general controls” authorized under the FD&C Act, including regulations pertaining to adulteration (section 501), misbranding (section 502), device registration (section 510), banned devices (section 516), and records/reports (section 519). Class I includes not only items as simple as elastic bandages, crutches, and thermometers, but also skull plate anvils, which are used for skull reconstruction, and the battery-powered artificial larynx.

General controls apply to each class of medical devices, but many devices require additional measures to ensure safety and effectiveness. When general controls alone are deemed insufficient to guarantee a device’s safety and effectiveness, but there is enough information to establish “special” controls, the FDA places it in Class II. Special controls can include performance standards, post-market surveillance, patient registries, guidance documents, and other recommendations. Examples of Class II devices include tests for sickle cell disease, stationary and mobile x-ray systems, and pneumatic surgical drills. Condoms, air handlers for surgical operating rooms, oxygenators used during cardiopulmonary bypass surgery, and dura substitute (material used to repair the membrane surrounding the brain) are also Class II devices.

Class III devices pose the highest degree of risk. Devices in Class III are used to support or sustain life, or their use “is of substantial importance” to prevent impairment to health, or poses “potential unreasonable risk of illness or injury.” To ensure safety and effectiveness, such devices require premarket approval (see below) by the FDA; that is, general and special controls alone are not enough to guarantee safety and efficacy. Devices in Class III include cranial electrotherapy stimulators, replacement heart valves, suctioning devices and tongs used to remove foreign objects from a patient’s airway, intrauterine devices (IUDs) for contraception, and soft contact lenses intended for extended wear.

It is a manufacturer’s responsibility to determine a device’s classification. The FDA maintains a product classification database, and 21 CFR Parts 862-892 lists 1,700 types of devices, organized by medical specialty into 19 “panels,” such as “Clinical chemistry and clinical toxicology devices” (part 862), “Gastroenterology-urology devices” (part 876), and “Radiology devices” (part 892). Entries at 21 CFR Parts 862-892 include a description of each device type, its intended use, and its class.

Under section 513(g) of the FD&C Act, manufacturers may submit a 513(g) Request for Information to petition the FDA for information about the regulatory requirements for a particular device and its classification. The FD&C Act gives the FDA 60 days to respond in writing to a request; the agency has said it intends to keep to the prescribed timetable.

Device clearance and approval processes

Because of the potential risks they pose, Class III devices face rigorous scientific and regulatory review via the premarket approval (PMA) pathway. Section 515 of the FD&C Act describes the PMA pathway, while regulations governing the process are outlined in 21 CFR Part 814. PMA applications require “many volumes of material,” according to the FDA, including a description of the device and its intended use, the results of both non-clinical and clinical studies, case reports, a description of the manufacturing process, proposed product labeling, and so forth.

Following a review of the application, if the FDA determines there is enough scientific evidence to provide reasonable assurance that the device can be used safely and effectively for its intended purpose(s), the agency approves the device for marketing. Class III devices that do not meet PMA requirements are not approved and may not be marketed; the FDA deems them “adulterated” under section 501(f) of the FD&C Act.

As noted, the FDA has determined that the risks associated with Class I and Class II devices can be managed via either general controls or general and special controls combined. Most Class I and II devices require premarket notification via the 510(k) pathway. Less rigorous than the PMA pathway, the 510(k) process is intended to demonstrate that a device is “substantially equivalent” to an existing device—called the predicate device—that is legally marketed for the same indication. Substantial equivalence refers to a product’s safety and efficacy vis à vis its predicate. As explained by the FDA, 2 devices are substantially equivalent when:

  • They have the same intended use and the same technological characteristics; or
  • They have the same intended use and different technological characteristics, but information submitted to the FDA about the new device does not raise new questions of safety and effectiveness and demonstrates that the new device is at least as safe and effective as its predicate.

As explained in 21 CFR Part 807.81, the FDA requires a 510(k) submission when a device is introduced to the market for the first time, when a change or modification to a marketed device could “significantly affect” its safety or effectiveness, and when there is a “major” change or modification to the intended use of a marketed device.

Following the FDA’s review of a 510(k) submission, the agency may take any of the following actions:

  • Issue an order declaring the device substantially equivalent to a predicate device. Such a device is considered “cleared” by the FDA;
  • Issue an order declaring that the device is not substantially equivalent to any legally marketed predicate device;
  • Request additional information; or
  • Tell the applicant that a 510(k) submission is not required (because the product is not regulated as a device or because it is exempt from premarket notification requirements).

If the FDA declares that a product is not substantially equivalent to an established device, the applicant may not legally market the device. The applicant may:

  • Collect new data and resubmit the 510(k);
  • Request Class I or Class II designation via the de novo process (explained below);
  • Petition for reclassification; or
  • Submit a PMA application.

Humanitarian device exemptions

The term “humanitarian use device” (HUD) refers to a device intended to treat or diagnose a disease or condition affecting not more than 8,000 people annually in the US. In some cases, the cost of developing a device for such a small patient group exceeds the returns a company would gain by marketing it. The FDA’s humanitarian device exemption (HDE) provides an incentive to HUD developers, waiving the evidence-of-effectiveness requirements that apply to PMA applications. (The FDA also waives user fees for HDEs.) HDE and PMA applications are otherwise similar; however, HDE applications must explain why the device would not be available without an exemption. Regulations regarding HUDs are found at 21 CFR 814 Subpart H.

De novo classification orders

A sponsor filing a de novo petition is asking the FDA to perform a risk-based evaluation to gain Class I or II status for a device. Under the Food and Drug Administration Modernization Act of 1997 (FDAMA), sponsors of low- to moderate-risk novel devices may request de novo classification after receiving a “not substantially equivalent” decision to a 510(k) submission. Sponsors may also take the “direct de novo” pathway, requesting de novo classification without submitting a 510(k) at all. The Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) introduced the “direct de novo” option.

Novel devices cannot be considered “substantially equivalent” to predicate devices—they do not have predicates. As explained in the FDA’s De Novo Classification Process (Evaluation of Automatic Class III Designation), “devices of a new type that FDA has not previously classified” are automatically considered Class III devices, “regardless of the level of risk they pose or the ability of general and special controls to assure safety and effectiveness.” Not having a predicate does not automatically mean a device is high risk, however. If there are data to support that a novel device poses only low to moderate risk, the sponsor can apply for de novo classification that, if granted, spares them the lengthy PMA process.

A de novo petition must include a description of the novel device and reasons for the recommended classification; the FDA has 120 days to make a determination. If the FDA grants the de novo request, the device is assigned to either Class I or Class II, establishing a new device “type” that may be marketed immediately and used as a predicate for future premarket notification 510(k) submissions. The FDA announces the new classification regulation in the Federal Register, specifying any relevant special controls (for Class II devices). If the FDA declines a de novo request, the device remains Class III and may not be marketed without a PMA or a product development protocol filing.

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