Which FDA route a device qualifies for, 510(k), De Novo or PMA

The premarket route for a device turns on its classification under section 513 of the Federal Food, Drug, and Cosmetic Act and on whether a legally marketed predicate device exists. A device of a type already in class I or class II, and not exempt, reaches the market through a premarket notification under 21 CFR part 807 subpart E. A class III device requires an approved premarket approval application under 21 CFR part 814. A device of a new type whose risks general controls or general and special controls can address is classified through the De Novo process under section 513(f)(2) of the act.

How the three routes divide

Part 814 applies to any class III device, unless exempt under section 520(g) of the act, that was not on the market before 28 May 1976 and is not substantially equivalent to a device on the market before that date or to a device first marketed on or after that date that has been classified into class I or class II.¹ It also applies to a device required to have an approved PMA or a declared completed product development protocol under a regulation issued under section 515(b), and to a device regulated by FDA as a new drug or antibiotic drug before 28 May 1976.¹

The notification route mirrors the same test from the other side. Section 807.81(a)(1) treats a device as being introduced for the first time where it is not of the same type as, or is not substantially equivalent to, a device in commercial distribution before 28 May 1976 or a later device since reclassified into class I or class II.² A device that fails the substantial equivalence test falls to class III by operation of the statute unless it is classified into class I or class II through De Novo.

When a premarket notification is required

Each person required to register an establishment under § 807.20 must submit a premarket notification at least 90 days before introducing a device into interstate commerce for commercial distribution in three situations.² The first is where the device is being introduced into commercial distribution for the first time. The second is where the device is being introduced for the first time by a person required to register, whether or not the first criterion is met. The third is where a device already in commercial distribution is about to be significantly changed or modified in design, components, method of manufacture or intended use.²

Section 807.81(a)(3) specifies what counts as a significant change. A change that could significantly affect the safety or effectiveness of the device qualifies. That includes a significant change in design, material, chemical composition, energy source or manufacturing process. A major change or modification in the intended use also qualifies.²

Several situations remove the obligation. No premarket notification is required for a device for which a PMA under section 515, or a petition to reclassify under section 513(f)(2), is pending before FDA.² Where a predetermined change control plan has been cleared under section 515C of the act, a change consistent with that plan does not require a notification.² A custom device within the meaning of section 520(b) is exempt, as is a distributor placing a device into commercial distribution for the first time under its own name where the device was in commercial distribution before 28 May 1976 or another person filed a notification.² Section 807.65 lists classes of persons exempt from registration. These include manufacturers of raw materials or components who would otherwise not be required to register, manufacturers of devices for veterinary use only and persons who manufacture devices solely for research, teaching or analysis and do not introduce them into commercial distribution.²

Content and outcome of a premarket notification

Section 807.87 sets the required content of a 510(k) submission. The submission must contain the following.

• The device name, including trade or proprietary name and the common or usual or classification name.
• The establishment registration number of the owner or operator, if applicable.
• The class into which the device has been put under section 513 and, if known, its panel.
• Action taken to comply with any performance standard under section 514.
• Proposed labels, labeling and advertisements sufficient to describe the device, its intended use and its directions for use.
• A statement of how the device is similar to or different from comparable products in commercial distribution, with supporting data.
• Supporting data on the consequences of any significant change or new indication for use.
• A 510(k) summary under § 807.92 or a 510(k) statement under § 807.93.
• A financial certification or disclosure statement under part 54.
• Statements about compliance of any supporting clinical investigations with parts 50, 56 and 812, or with § 812.28 for investigations conducted outside the United States.
• A truthfulness and accuracy statement.

Each submission is made as a single version in electronic format, separately for each product, and is designated “510(k) Notification” in the cover letter.² Where substantial equivalence is claimed to a device classified into class III under section 513(b) that was marketed before 1 December 1990 and for which no section 515(b) regulation has issued, the submission must include a class III summary and a class III certification in the form set out in § 807.94.²

FDA determines substantial equivalence using the criteria in § 807.100(b). The device must have the same intended use as the predicate. It must either have the same technological characteristics as the predicate, or have different technological characteristics supported by data establishing that it is as safe and as effective as a legally marketed device and raising no different questions of safety and effectiveness.² The predicate must not have been removed from the market at the Commissioner’s initiative or found misbranded or adulterated by judicial order.²

FDA may issue an order of substantial equivalence, issue an order of not substantially equivalent or request additional information. It may also withhold decision pending a part 54 certification or advise that notification is not required. Until an order declaring the device substantially equivalent is received, the applicant may not market the device.² If requested additional information is not submitted within 30 days of the request, the Commissioner will consider the notification withdrawn.² FDA makes the 510(k) summary public within 30 days of a determination of substantial equivalence.²

A determination of substantial equivalence is an order under section 510(k) of the act. The regulation states that such a determination does not denote official approval, and that any representation creating an impression of official approval on that basis is misleading and constitutes misbranding.²

De Novo classification where no predicate exists

The De Novo route rests on section 513(f)(2) of the act, which allows a device automatically designated class III for want of a predicate to be classified into class I or class II. The regulations in part 807 recognise it in several places. A de novo classification petition is one of the premarket submission types for which FDA assigns a number.² A premarket notification is not required while a petition to reclassify under section 513(f)(2) is pending.² Where the Commissioner determines that a device described in a confidential notification is class III and cannot be marketed without premarket approval or reclassification, the existence of the submission is not disclosed unless a section 513(f)(2) petition is submitted.²

Guidance from the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research describes the process for evaluation of automatic class III designation.³ That guidance states FDA’s current thinking and binds neither FDA nor industry.³ A device classified through this route becomes available as a predicate, since § 807.92(a)(3) treats a device reclassified from class III to class II or class I as a legally marketed device for comparison purposes.²

Premarket approval

A PMA is required for the class III devices described in § 814.1(c).¹ A class III device for which FDA has declared a product development protocol completed is considered to have an approved PMA.¹ The application is signed by the applicant or an authorised representative, and an applicant without a place of business in the United States must have the application countersigned by a representative who resides or maintains a place of business there.¹

The application is submitted in electronic format as a single version with a table of contents and separate sections on nonclinical laboratory studies and on clinical investigations.¹ The summary required by § 814.20(b)(3) covers the following.¹

• indications for use
• device description
• alternative practices and procedures
• marketing history
• a summary of the nonclinical and clinical studies
• conclusions demonstrating valid scientific evidence within the meaning of § 860.7

Where clinical investigations conducted outside the United States support the application, § 812.28 applies.¹ A PMA based solely on foreign clinical data may be approved where the data are applicable to the United States population and medical practice, the investigators are of recognised competence, and the data can be considered valid without an on-site inspection or can be validated by one.¹

PMA review timeframes and postapproval duties

FDA notifies the applicant within 45 days of receipt whether the application has been filed, and the 180-day review period runs from the date of filing.¹ Grounds for refusing to file include an incomplete application, omission of items required by § 814.20 without adequate justification and a pending 510(k) for the same device where FDA has not determined whether § 814.1(c) applies. A false statement of material fact and the absence of a part 54 statement are also grounds.¹ An applicant may request an informal conference within 10 working days of a refusal to file.¹

Within 180 days of filing, FDA issues an approval order, an approvable letter, a not approvable letter or an order denying approval.¹ A major amendment may extend the review period by up to 180 days.¹ Where FDA requests an amendment and receives no written response within 180 days, the application is considered voluntarily withdrawn.¹ FDA may refer the application to an advisory panel on its own initiative and will do so on request unless the application substantially duplicates information already reviewed by a panel.¹

An approved device may not be manufactured, stored, labeled, distributed or advertised inconsistently with the conditions in the approval order.¹ Postapproval requirements may include the following.¹

• restrictions on sale and use
• continuing evaluation and periodic reporting
• labeling warnings
• identification codes
• record maintenance
• batch testing

A change affecting safety or effectiveness requires a PMA supplement, unless it is consistent with a predetermined change control plan approved under section 515C or falls within another alternative FDA has allowed.¹

Humanitarian device exemption

Subpart H of part 814 provides a separate route for a device intended to benefit patients in the treatment or diagnosis of a disease or condition affecting not more than 8,000 individuals in the United States per year.¹ Approval involves two steps. The applicant first obtains humanitarian use device designation from FDA’s Office of Orphan Products Development, which acts within 45 days of receiving the request.¹ The applicant then submits a humanitarian device exemption application to the Office of Product Evaluation and Quality, CBER or CDER, as applicable.¹

The application must explain why the device would not be available without the exemption and state that no comparable device is available.¹ It must explain why the probable benefit to health outweighs the risk of injury or illness. Labeling must bear the statement that the device is authorized by Federal law for the stated use and that its effectiveness for that use has not been demonstrated.¹ Where the amount charged for the device exceeds $250, the application must include a report by an independent certified public accountant or an attestation verifying that the charge does not exceed the costs of research, development, fabrication and distribution.¹ An applicant seeking approval of a non-humanitarian use of the same device submits a PMA under § 814.20 or a premarket notification under part 807.¹

Questions people also ask

What makes a device eligible for the 510(k) route rather than premarket approval?

Eligibility rests on substantial equivalence to a legally marketed predicate device. Under § 807.100(b), the device must have the same intended use as the predicate and either the same technological characteristics or different characteristics supported by data showing it is as safe and as effective and raising no different questions of safety and effectiveness.² Premarket approval applies to class III devices described in § 814.1(c), including those that are not substantially equivalent to a pre-amendments device or to a device since classified into class I or class II.¹

Can a device be shipped while its 510(k) is under FDA review?

No. Section 807.100(a)(5) provides that until the applicant receives an order declaring the device substantially equivalent, the applicant may not proceed to market it.² The notification itself must be submitted at least 90 days before the proposed introduction into interstate commerce for commercial distribution.²

What qualifies as a predicate device?

Section 807.92(a)(3) describes a legally marketed device for comparison purposes as one legally marketed before 28 May 1976, one reclassified from class III to class II or class I, or one found substantially equivalent through the premarket notification process.² The predicate must not have been removed from the market at the Commissioner’s initiative or found misbranded or adulterated by judicial order.²

How long does FDA take to act on a premarket approval application?

FDA notifies the applicant within 45 days whether the application is filed, and the 180-day review period begins on the date of filing.¹ A major amendment, whether submitted by the applicant or at FDA’s request, may extend the review by up to 180 days.¹ At the end of review FDA issues an approval order, an approvable letter, a not approvable letter or an order denying approval.¹

When does a change to a marketed device require a new submission?

For a cleared device, § 807.81(a)(3) requires a new premarket notification for a change that could significantly affect safety or effectiveness or a major change in intended use. This does not apply where the change is consistent with a predetermined change control plan cleared under section 515C.² For an approved device, § 814.39(a) requires a PMA supplement before making a change affecting safety or effectiveness, with listed examples including new indications, labeling changes, sterilization changes and changes in performance or design specifications.¹

Footnotes

1. 21 CFR Part 814, Premarket Approval of Medical Devices. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-814 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴ ↩²⁵ ↩²⁶ ↩²⁷ ↩²⁸ ↩²⁹ ↩³⁰ ↩³¹

2. 21 CFR Part 807, Establishment Registration and Device Listing for Manufacturers and Initial Importers of Devices. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-807 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴ ↩²⁵ ↩²⁶

3. FDA guidance, Center for Devices and Radiological Health Center for Biologics Evaluation and Research, De Novo Classification Process (Evaluation of Automatic Class III Designation): Guidance for Industry and Food and Drug Administration Staff. 5 October 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/de-novo-classification-process-evaluation-automatic-class-iii-designation ↩ ↩²