What an FDA medical device submission contains

What a manufacturer files depends on the class of the device and on whether a legally marketed device of the same type exists. Four premarket routes appear in 21 CFR Parts 807, 814 and 860: a premarket notification under section 510(k), a De Novo classification request, a premarket approval application (PMA) and a humanitarian device exemption (HDE) application. Each is filed as a single version in electronic format. Each ends in an order from FDA, and the form of that order differs by route.

Which submission applies

Class I covers devices subject only to the general controls of the Federal Food, Drug, and Cosmetic Act. Class II covers devices for which special controls, together with general controls, provide reasonable assurance of safety and effectiveness. Class III covers devices for which premarket approval is or will be required under section 515.¹

Section 807.81(a) requires a premarket notification from each person required to register an establishment. It is due at least 90 days before that person proposes to begin introduction of the device into interstate commerce for commercial distribution. Three triggers appear in that paragraph: first commercial distribution of the device type, first commercial distribution by that person and a significant change or modification. A change that could significantly affect safety or effectiveness counts as significant, as does a major change in intended use. Section 807.81(b)(1) removes the requirement where a PMA or a reclassification petition is pending, and where a change is consistent with a predetermined change control plan cleared under section 515C.

A De Novo request is available for a single device type after a not substantially equivalent determination, or where the requester determines there is no legally marketed device on which to base a substantial equivalence determination.¹ Part 814 applies to class III devices described in § 814.1(c), including devices first marketed after 28 May 1976 that are not substantially equivalent to a preamendments device.

What a premarket notification contains

Section 807.87 sets out the contents of every 510(k).² The submission includes the following:

• the device name, being both the 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 under section 513 and the panel if known, or a statement that the device has not been classified with the basis for that determination,
• the action taken to comply with performance standard requirements 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, accompanied by supporting data,
• supporting data addressing the consequences of a significant change or modification, or of a new or different 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 on the conduct of clinical investigations, referencing Parts 50, 56 and 812 for United States investigations and § 812.28 for investigations conducted outside the United States,
• a class III summary and a class III certification where the claimed predicate is a class III device under section 513(b) marketed before 1 December 1990 with no final regulation requiring premarket approval.
• a statement that all data and information in the submission are truthful and accurate and that no material fact has been omitted.

Section 807.87(e) states that photographs or engineering drawings should be supplied where applicable. That wording is recommendatory. Under § 807.87(m) the Commissioner may request additional information needed for the substantial equivalence finding. If that information is not submitted within 30 days of the request, the Commissioner considers the premarket notification withdrawn.²

Format of a 510(k) and its summary documents

Section 807.90 requires the submission as a single version in electronic format, separately for each product the manufacturer intends to market. The cover letter designates it “510(k) Notification”. Devices regulated by the Center for Devices and Radiological Health go to the address displayed at the CDRH submission address page, with separate addresses for devices regulated by the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research.

The 510(k) summary under § 807.92 must be detailed enough to explain the basis for a substantial equivalence determination. It identifies the submitter and the device, identifies the legally marketed predicate and describes the device and its intended use. Where performance data support the determination, the summary discusses the nonclinical and clinical tests relied on and the conclusions drawn from them. Section 807.92(c) provides that the summary should sit in its own section, beginning on a new page and clearly identified.

The alternative to a summary is the 510(k) statement in § 807.93, a signed certification that the submitter will make all safety and effectiveness information in the submission available within 30 days of a request by any person, once the device is found substantially equivalent. The information released is a duplicate of the submission, excluding patient identifiers and trade secret or confidential commercial information as defined in § 20.61. The class III certification in § 807.94 carries prescribed wording about a reasonable search of known information, signed and placed at the start of the class III summary section.

What a De Novo request contains

A De Novo request is provided as a single version in electronic format, signed by the requester or an authorized representative and designated “De Novo Request” in the cover letter. All supporting content must be written in or translated into English.¹ The items required by § 860.220(a) include a table of contents, administrative information and the regulatory history of the device. The regulatory history identifies the following, or states that there were none.¹

• prior 510(k)s
• PMAs
• HDEs
• IDEs
• requests for designation
• section 513(g) requests
• emergency use authorizations
• pre-submissions
• earlier De Novo requests

The request also gives the device name, the indications for use, a complete device description and a description of existing alternative practices and procedures.¹ For a device with no earlier 510(k), the classification summary describes the searches used to establish that no legally marketed device of the same type exists. It lists the following for potentially similar devices.

• classification regulations
• PMAs
• HDEs
• 510(k)s
• emergency use authorizations
• product codes

A requester may omit an item by justifying the omission under § 860.220(c).

What a premarket approval application contains

The applicant or an authorized representative signs the PMA. Where the applicant does not reside or have a place of business in the United States, an authorized representative in the United States countersigns and is identified by name and address.³ The application is submitted in electronic format as a single version, and includes the applicant’s name and address.³ It carries a table of contents specifying the volume and page number for each item, with separate sections on nonclinical laboratory studies and on clinical investigations involving human subjects.³ The applicant includes any material it believes to be trade secret or confidential commercial information and identifies that material as such.³

The summary required by § 814.20(b)(3) must let a reader gain a general understanding of the data in the application. It states the indications for use and describes the patient population, explains how the device functions and its significant physical and performance characteristics, describes existing alternative practices and procedures and gives the foreign and United States marketing history.³ Omissions elsewhere in the application must be justified under § 814.20(d). Section 814.37(b)(2) allows FDA to request an amendment with information on pediatric uses required under § 814.20(b)(13).

An HDE under § 814.104(b) carries all of the information required under § 814.20(b), with stated exceptions for clinical data. It adds the humanitarian use device determination from the Office of Orphan Products Development, an explanation of why no comparable device is available and an explanation of why probable benefit outweighs the risk of injury or illness.

How review works

For a 510(k), § 807.100(a) lists the possible FDA actions. These are an order declaring the device substantially equivalent, an order declaring it not substantially equivalent and a request for additional information. The FDA may also withhold a decision pending a Part 54 certification or advise that a premarket notification is not required. Until the applicant receives an order declaring the device substantially equivalent, it may not market the device. The criteria in § 807.100(b) turn on the same intended use and either the same technological characteristics or data showing the device is as safe and as effective without raising different questions of safety and effectiveness. Section 807.97 provides that any representation creating an impression of official approval from a substantial equivalence determination is misleading and constitutes misbranding.

For a De Novo request, FDA notifies the requester within 15 days whether the request has been accepted. Grounds for refusing acceptance include an open or pending premarket submission for the same device, incompleteness on the face of the request and a request covering more than one device type.¹ Within 120 days after acceptance FDA grants or declines the request by order.¹ FDA may inspect relevant facilities to confirm how data were collected and to assess implementation of the Quality Management System Regulation in Part 820.¹ A grant is published in the Federal Register within 30 days, with any special controls.¹ Failure to respond fully to a request for additional information within 180 days results in withdrawal.¹

For a PMA, filing is a threshold determination that the application is complete enough for substantive review. FDA notifies the applicant within 45 days whether the application has been filed, and the 180-day review period runs from the filing date. Within that period FDA issues an approval order, an approvable letter, a not approvable letter or an order denying approval. A major amendment may extend the review by up to 180 days. FDA may refer the application to an advisory panel on its own initiative and must do so on the applicant’s request, unless the application substantially duplicates information a panel has already reviewed. An HDE runs on shorter clocks: a filing decision within 30 days and an FDA action within 75 days of acceptance for filing.

Safety and effectiveness decisions rest on valid scientific evidence as described in § 860.7, which is the standard applied in PMA denials under § 814.45(c) and in De Novo decisions under § 860.260(e).¹

Questions people also ask

What is the difference between a 510(k) clearance and a PMA approval? A 510(k) results in an order finding the device substantially equivalent to a legally marketed predicate, using the criteria in § 807.100(b). A PMA results in an order approving the device based on valid scientific evidence of reasonable assurance of safety and effectiveness. Section 807.97 treats any claim of official approval arising from a substantial equivalence determination as misbranding.

Does a 510(k) have to include clinical data? Section 807.87(f) requires data supporting the statement of similarity to and difference from comparable marketed products, without specifying that the data be clinical. Where clinical data are included, § 807.87(j) requires statements on compliance with Parts 50, 56 and 812 for investigations in the United States and with § 812.28 for investigations conducted elsewhere.²

How long does FDA have to act on a De Novo request? FDA notifies the requester within 15 days whether the request is accepted, then issues an order granting or declining the request within 120 days of acceptance.¹

What happens when FDA asks for more information? The day counts differ by route. In a 510(k), information requested under § 807.87(m) that is not supplied within 30 days causes the notification to be treated as withdrawn.² In a PMA, a written response is due within 180 days of the request, and in an HDE within 75 days.

Can one submission cover several products? Section 807.90(d) requires a separate premarket notification for each product the manufacturer intends to market. A De Novo request covers a single device type, and FDA may refuse to accept a request that covers devices of more than one type.¹

Footnotes

1. 21 CFR Part 860, Medical Device Classification Procedures. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-860 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³

2. 21 CFR 807.87, Information required in a premarket notification submission. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-807/subpart-E/section-807.87 ↩ ↩² ↩³ ↩⁴

3. 21 CFR 814.20, Application. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-814/subpart-B/section-814.20 ↩ ↩² ↩³ ↩⁴ ↩⁵