FDA Approved or Cleared Medical Device – Chutes and Ladders

Commercializing your medical device in the US market requires submitting marketing applications to the FDA to become an FDA Approved or Cleared Medical Device.

The content of your FDA submission is determined by how your medical device is classified into one of three Classes (I, II, or II), based on the degree of risk it presents. If your product falls into the Class I/II exemptions, it will only require device registration and listing with FDA. For Class II and III devices, there are several pathways to market.

The two most common forms of premarket submissions are the Premarket Notification 510(k) and the Premarket Approval (PMA) submissions. Another less common premarket submission is the De Novo Request submission. Each of these submission types results in a decision by the FDA that clears [510(k)], approves [PMA], or grants [De Novo] marketing rights to the successful Sponsor.

This blog looks at all of these submission types to understand the different pathways to FDA Approved or Cleared Medical Device status and access to the market for devices in the US.

510(k)

A 510(k) submission demonstrates that the device to be marketed is at least as safe and effective (substantially equivalent) to a legally marketed device (predicate) that is not subject to PMA. There are three types of 510(k) submissions including:

• Traditional 510(k): used when a new device is substantially equivalent to a predicate device already cleared for marketing in the US, or a modification to a previously cleared 510(k) device. Not all types of modifications require a new 510(k), but changes that impact safety, efficacy, or the intended use must be considered.
• Special 510(k): used to facilitate the submission, review, and clearance of a change to a manufacturer’s own legally marketed predicate device. It utilizes the Design Controls aspect of the Quality System Regulation, 21 CFR Part 820; the methods to evaluate changes need to be well-established and the results must be able to be reviewed in a summary or risk analysis format.
• Abbreviated 510(k): used when an FDA guidance document exists, special controls for the device have been established, or when the FDA has recognized relevant consensus standards (or all three). Summary reports on the use of standards, guidance documents and/or special controls or declarations of conformity to FDA recognized standards must be included with the submission..
• Safety and Performance Based Pathway: this is an expansion of the Abbreviated 510(k) program for certain, well-understood device types. The new device must have the same indications for use and technological characteristics as the identified predicate, and meet all the FDA-identified performance criteria.

The FDA processes 510(k) submissions in a range of 30 days (Special 510(k)) to 90 days (Traditional and Abbreviated 510(k)s). Applications are subject to the FDA’s acceptance review. Traditional, Special, and Abbreviated 510(k)s require the same 510(k) user fee. The Standard Fee is $12,432 and the Small Business Designation Fee is $3,108. You cannot market your device until it is cleared by the FDA and is an FDA Approved or Cleared Medical Device.

PMA

The PMA is the most stringent of the device marketing applications, as it evaluates the safety and effectiveness of the highest risk medical devices, Class III, which include life-supporting and/or life-sustaining devices. PMA applications will include technical sections, usually divided into benchtop testing (non-clinical studies) and clinical investigations. PMA approval typically requires a facility inspection to confirm compliance to 21 CFR 820 prior to approval. There are several types of PMAs and PMA Supplements including:

• Traditional PMA: an original PMA application contains a considerable amount of objective evidence to support the safety and effectiveness of the device including the device description, indications for use, intended use, nonclinical and clinical studies, case report forms, manufacturing methods and labelling
• Modular PMA: for products that are in the early stages of a clinical study. The contents are submitted to the FDA in separate modules (i.e. preclinical, clinical, and manufacturing) upon the Sponsor’s completion of each module and collectively form the entire Modular PMA.
• Product Development Protocol (PDP): used for well-established products in the industry,it requires an agreement between the Sponsor and the FDA regarding the objective evidence required by the FDA to demonstrate the safety and effectiveness of the new device. The Sponsor must comply with reporting milestones (e.g. design and development activities, outputs and acceptance criteria for the outputs). Once the FDA reviews milestone reports, the FDA declares the PDP to be completed, and the Sponsor is considered to have an approved PMA.

The FDA has 180 days to accept or reject the PMA application. The Standard Fee for a Traditional PMA is $365,657 and the Small Business Designation Fee is $91,414. There are additional fees for PMA supplements, which can be found here.

Humanitarian Device Exemption (HDE)

A Humanitarian Use Device (HUD) is for Class III devices that are intended to benefit patients with rare diseases or conditions. An HDE application is similar in both form and content to a PMA application. However, it is exempt from the effectiveness requirements of a PMA and the Sponsor is not required to include results of scientifically valid clinical investigations, but still needs to provide proof of safety. The FDA review cycle for an HDE application is 75 days.

De Novo Application

There are two De Novo options for companies with novel devices of low or moderate risk that do not have a valid predicate device. The company can submit a 510(k) to the FDA and after receipt of a “Not Substantially Equivalent” determination, the De Novo request can be made; or the company can submit a De Novo request without first submitting a 510(k).

Once a De Novo request is successfully granted, the FDA creates a classification for the device, a regulation if necessary, and identifies any special controls required for future premarket submissions of substantially equivalent devices. The device can then be marketed and used as a predicate for future 510(k) submissions.

The FDA review cycle for a De Novo application is 120 days. The Standard Fee for a De Novo application is $109,697 and the Small Business Designation Fee is $27,424.

Breakthrough Device Program

This is a voluntary program for certain medical devices that provide more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. The goal is to provide timely access to these medical devices by speeding up their development, assessment, and review of their premarket submissions, while preserving the standards for PMA, 510(k), and De Novo marketing authorization. Sponsors will receive feedback from FDA experts and identify areas of agreement in a timely way. Sponsors can also expect a prioritized review of their submission. A Breakthrough Designation request can be sent by the Sponsor for their device at any time before its marketing application submission.

Safer Technologies Program (STeP) for Medical Devices

This new, voluntary program is modelled after the Breakthrough Devices Program, reducing the time it takes to develop and obtain marketing authorization for eligible medical devices. STeP focuses on devices for treating or diagnosing non-life-threatening or reasonably reversible conditions. It is intended for devices that are reasonably expected to significantly improve the safety of currently available medical treatments or diagnostics through innovative features. Sponsors are encouraged to submit a STeP entrance request (via the Q-submission process) prior to sending the marketing application to receive the most benefit from the program. The FDA review cycle is 60 days. The FDA anticipates accepting entrance requests as of March 8, 2021.

Additional Support for Submissions

Investigational Device Exemption (IDE)

An IDE allows the investigational device to be used in a clinical study to collect safety and effectiveness data required to support a PMA or 510(k) submission to the FDA. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated. Clinical studies with devices of significant risk must be approved by the FDA and by an Institutional Review Board (IRB) before the study can begin. If the study is low risk, an IDE is not required, only IRB approval.

Q-Submission Program (Pre-Submissions / Pre-Subs)

The Q-Submission Program offers different mechanisms to allow Sponsors to request feedback from the FDA in the forms of a written response and/or a face-to-face or a virtual meeting. Pre-Subs are used for various reasons including obtaining FDA feedback prior to intended pre-market submissions, determining if a clinical study is a significant risk or non-significant risk, or is exempt from IDE regulations, for submission issues, and FDA feedback to specific questions related to a pending submission or protocol.

A Pre-Sub is appropriate when FDA’s feedback on specific questions is necessary to guide product development and/or submission preparation. The FDA recommends identifying 3-4 substantial topics in your Pre-Sub, as this facilitates more productive meetings and results in more effective conversations and feedback. This will ensure that FDA has sufficient time to provide an in-depth response to each question and to enable focused meetings.

Postmarket Activities

Once the FDA has cleared [510(k)], approved [PMA], or granted [De Novo] marketing rights for your medical device, certain requirements and regulations must be followed. These include such things as tracking systems, reporting of device malfunctions, serious injuries or deaths, and registering the establishments where devices are manufactured or distributed. Postmarket requirements also include postmarket surveillance studies required under section 522 of the Federal Food, Drug and Cosmetic Act as well as post-approval studies required at the time of approval of a PMA, HDE, or PDP application.