By Seth A. Mailhot and Peter S. Reichertz

On December 31, 2012, the U.S. Food and Drug Administration (FDA) issued two new guidance documents on the minimum threshold of acceptability for medical device premarket submissions, which are titled “Refuse to Accept Policy for 510(k)s,” and “Acceptance and Filing Reviews for Premarket Approval Applications (PMAs).” These guidance documents detail the conditions under which a Premarket Notification [510(k)], or a Premarket Approval application [PMA] will be accepted for substantive review.

The new guidance documents are intended to conserve FDA’s limited resources by focusing FDA review on what FDA considers to be “complete submissions.” FDA believes the changes to the 510(k) and PMA processes will make them more efficient, and help FDA achieve its medical device user fee performance goals.

Changes to the 510(k) Process

FDA modified its 510(k) Refuse to Accept (RTA) policy to include an early review against specific acceptance criteria. According to the guidance, FDA plans to notify submitters within the first 15 calendar days after receipt of the 510(k) about whether it is administratively complete. If the 510(k) is deficient, FDA intends to identify the missing element(s) for submitters by providing a copy of FDA’s checklist.

The 510(k) submitter may respond to the RTA notification by providing the missing information, which will be included in the file under the originally assigned 510(k) number. Providing a response to an RTA notification does not trigger a new submission, or require payment of a second user fee. FDA notes that a response to an RTA notification does not require re-sending the entire 510(k) submission, although in some situations FDA will request that the complete 510(k) submission be re-sent. As is consistent with FDA’s policy on responding to 510(k) deficiencies, if a response to the RTA notification is not received within 180 days of the date of the RTA notification, FDA will consider the 510(k) to be withdrawn and the submission will be closed in the system.

FDA’s review checklist covers three primary areas, which are described briefly below. The checklist will also include a section to confirm that the type of 510(k) submitted is appropriate, if an Abbreviated or Special 510(k) has been submitted. The other areas covered by the checklist are:

  • Preliminary Questions
    • FDA will determine whether the product described in the 510(k) is a medical device appropriate for submission as a 510(k), including evaluating its status as a combination product, and researching to see if a similar device has been submitted under a PMA. FDA will also confirm that the submission is not subject to its Application Integrity Policy, which suspends review of clinical data on the suspicion of fraud, and verify that the 510(k) was sent to the correct Center.
  • Organizational Elements
    • FDA will review the submission to determine if it is appropriately formatted. This involves confirming that a Table of Contents is included, that sections are appropriately titled, that page numbers are provided, and that the type of 510(k) is identified. FDA notes that the failure to follow these formatting conventions would generally not result in an RTA designation.
  • Elements of a Complete Submission (called “RTA Items” in the guidance)
    • FDA breaks these items down into several subsets:
      • Administrative
        • This includes evaluating whether all of the information has been submitted in English, and whether the necessary forms and signatures have been provided.
      • Device Description
        • This includes whether a description of the principle of operation and mechanism of action for achieving the intended effect are described. 
      • Substantial Equivalence Discussion
        • This includes whether the 510(k) identifies a predicate(s) device.
      • Proposed Labeling
        • This includes whether the submitted labeling provides a description of the device, its intended use, and directions for use. 
      • Sterilization
      • Shelf Life
      • Biocompatibility
      • Software
      • EMC and Electrical Safety
      • Performance Data – General
      • Performance Characteristics (this subset is relevant to in vitro diagnostic devices)

After a response to the RTA notification is received by FDA, FDA will conduct another acceptance review according to the same procedure (including the 15 calendar day timeframe). The subsequent acceptance review will assess whether the new information makes the submission complete according to FDA’s checklists. If the submission is still deficient, FDA will provide another checklist identifying the missing item(s).

The FDA review clock starts once the 510(k) is formally accepted. The start date of the review will be set as the date that the most recent submission resulting in acceptance was received by FDA (provided the user fee has been paid, and the required electronic copy was provided). Once the 510(k) is under substantive review, the time used by FDA to conduct the acceptance review will be included as part of the 60 calendar day timeframe for FDA’s Substantive Interaction goal. The Substantive Interaction goal is communication with the applicant to resolve any outstanding deficiencies through an interactive review, which occurs after the FDA has performed a complete review of the submission.

Changes to the PMA Process

There are fewer changes to the existing PMA filing process, compared to the changes made to the 510(k) process. As the regulations on PMA filing criteria have not changed, the new guidance document is not significantly different from the previous PMA filing checklist and guidance document. The “preliminary questions” remain the same, and the “filing review questions” are now separated into “acceptance decision questions” (i.e., whether the file is administratively complete) and “filing decision questions” (i.e., whether the data are consistent with the protocol, final device design, and proposed indications).

The preliminary review of PMA applications will now take place in two phases. First, FDA will conduct an acceptance review, which involves assessment of the completeness of the application. Under the new guidance, FDA plans to inform applicants in writing within the first 15 calendar days of receipt of the application as to whether any required elements are missing, and identifying them.

Second, FDA conducts a filing review, which determines the basic adequacy of the technical elements of the PMA. In order for the submission to be filed, the application must be sufficiently complete to permit a substantive review. Once the filing review is complete, FDA intends to notify the applicant in writing within 45 calendar days as to whether the PMA has been filed or not.

One additional change in the PMA filing process involves how FDA will handle the manufacturing section. Under the previous guidance, FDA stated that it would still allow a PMA to be filed despite a delay in the submission of the manufacturing section of the PMA. Submission of the manufacturing section could be submitted up to 90 days after the rest of the PMA was sent. Under the new guidance, the manufacturing section is now included in the checklist for original PMAs and panel-track supplements involving a new manufacturing site or substantially different manufacturing procedures.

Sheppard Mullin Richter and Hampton LLP has experience in preparing and prosecuting new product submissions before the FDA, including those for medical devices. Our FDA team can also help to develop regulatory strategies for marketing FDA-regulated products. If you have any questions regarding these new guidance documents, please contact the authors.