United States National Companion Guide

• 510(k) Pathway
  • If the intended use and technological characteristics of a device are substantially similar to its predicate device, robust non-clinical safety and efficacy data may be sufficient for approval; however, clinical data may be required to prove substantial equivalence (SE).
  • Any clinical data submitted should comply with standards for valid scientific evidence (21 CFR 860.7(c)(2)) and may include pre- and post-market clinical trial data, published or unpublished scientific studies, and reports of clinical use (electronic health record (EHR), insurance claims, adverse event databases, and registries) for either the device under consideration or a substantially similar device.
  • Companies can engage with the FDA via the pre-submission process to obtain feedback on the types of evidence necessary for a particular device.
  • Further details and examples can be found in the FDA Guidance Documents:
    • Recommendations for the use of clinical data in Premarket Notification [510(k)] Submissions
    • Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics
    • 510(k) Program Guidance
• De Novo classification request
  • While the majority of products undergoing the De Novo process do present the FDA with clinical data, there are no specific “hard” targets for outcome thresholds.
  • Outcomes from novel clinical investigations are not always required for a De Novo request.
  • When data is provided to the FDA, whether it is clinical or non-clinical, it must be sufficient to establish safety and efficacy. Benefit-risk determinations in medical device premarket approval and De Novo classifications play a critical factor in determining appropriateness.
  • Companies are encouraged to engage with the FDA via the pre-submission process in order to obtain feedback on the types of evidence necessary for a particular device.
• Premarket approval application (PMA)
  • The majority of devices that proceed through the PMA process will require clinical data for approval.
  • Companies are encouraged to engage with the FDA via the pre-submission process to obtain feedback on the types of evidence necessary for a particular device.
  • The requirements for using data generated outside of the US (OUS) in support of submitting a PMA are notably stringent. According to 21 CFR 814.15, clinical data from OUS sources can be considered in support of a PMA if the following conditions are met: (1) the OUS clinical data are relevant and applicable to the US population and medical practice; (2) the studies were conducted by clinical investigators of recognized competence; and (3) the data are deemed valid without the need for an on-site inspection by the FDA or, if the FDA considers such an inspection to be necessary, the FDA can validate the data through an on-site inspection or other appropriate means.

Related to the use of data generated outside of the US:

• The FDA’s 510(k), De Novo, and PMA programs allow for the use of OUS data, as long as the study population and protocol conform to key requirements. As discussed previously, the standard for using data generated OUS is rigorous, particularly to verify that the device is safe and effective for the US population. Further insights are provided in 21 CFR 812.28.
  • The FDA makes a general statement regarding the acceptance of foreign data in its guidance, Acceptance of Clinical Data to Support Medical Applications and Submissions: Frequently Asked Questions: “FDA does not intend to regulate clinical investigations conducted OUS. We expect that foreign clinical investigations will be conducted in accordance with local laws and regulations. The requirements outlined in the rule allow the flexibility needed to accommodate those laws and regulations. The application of a GCP [good clinical practice] standard would be in addition to the local laws and regulations to the extent that the local laws and regulations do not incorporate such a standard. If needed, the rule allows sponsors and applicants to explain why GCP was not followed and to describe the steps taken to ensure that the data and results are credible and accurate and that the rights, safety, and well-being of human subjects have been adequately protected.”

A more complete list of resources may be found in DiMe’s Library of Digital Health Regulations and on the FDA’s Digital Health Center of Excellence website.

The federal regulatory agency in the United States is the Food and Drug Administration (FDA). The FDA is responsible for “assuring the safety, efficacy, and security” of human and veterinary drugs, medical devices, biological products, and products that emit radiation, as well as cosmetics and the US food supply.

The FDA offers extensive guidance on regulatory requirements and product submission processes on its website. These resources include guidance documents addressing regulatory pathways and common questions.

Review timelines vary according to the program through which a product is submitted. Examples of review timelines include:

510(k) Program: After a company submits appropriate documentation to the FDA related to the 510(k) pathway, the FDA will issue an acknowledgment letter indicating the official date of receipt of the submission and the assigned 510(k) number.

• Within 15 calendar days, the FDA will issue an Acceptance Review result indicating whether the submission has been accepted for Substantive Review. During the Substantive Review, the FDA will contact the submitter within 60 days of receipt of the application to initiate an Interactive Review and/or request additional information.
• If additional information is requested, the submitter has 180 calendar days to provide it; failure to provide all requested additional information within that time will result in the deletion of the 510(k) submission.
• The FDA’s goal is to render a decision on 510(k) applications within 90 “FDA Days” of application receipt. If additional information is requested at either review stage, the company has 180 days to provide it; no additional time will be granted.

De Novo Classification Request: Upon receipt of a request, the FDA will issue an Acceptance Review notification within 15 calendar days. If accepted for Substantive Review, the FDA’s goal is to render a decision within 150 FDA days. If additional information is requested at either review stage, the company has 180 days to provide it; no additional time will be granted.

PMA: The FDA will complete an acceptance and filing review within 45 days of receiving a PMA request. If cleared for in-depth review, the FDA’s goal is to render a decision within 180 days of completion of the filing review.

Breakthrough Devices Program: The FDA intends to request any additional necessary information within 30 days of receiving a request and to render a decision within 60 calendar days of receiving a request.

General questions can be submitted to the FDA by email. The FDA aims to respond, or acknowledge receipt and provide a timeline for response, within 5 days of receipt.

Yes, the FDA encourages pre-submission discussion. Companies may contact the FDA through the Q-Submission Program, which is a pathway for receiving formal feedback from the FDA prior to product submission, either written or in a meeting. Please refer to the guidance document outlining the Q-Submission process.

The majority of applications can be submitted online through the FDA’s Center for Devices and Radiological Health (CDRH) portal. As of October 1, 2023, all 510(k) submissions must be made through using the FDA’s electronic Submission Template and Resource (eSTAR). At this time, De Novo requests may be made electronically through eSTAR or by mail through eCopy (instructions), while PMA submissions must be made through eCopy. Q-submission and Breakthrough Device Designation requests are also made through the CDRH portal.

The FDA’s main support structure for regulatory applications is through the Q-submission process, outlined above. The agency will engage with companies during the submission process as outlined in the guidance documents for each pathway.