Nuts and Bolts of 510(K) Submissions

A 510(k) is pre-market notification of medical devices to the US FDA. The number “510” refers to section of the Food, Drug and Cosmetic Act. “k” is the subsection specific to pre-market notification. Details regulating the process, however, are found in 21 CFR §807.
The current device classification system consists of three-letter product codes for each device type. Each classification is designated as Class I, Class II or Class III. Class I devices are considered low risk and require only “general controls.” Class II devices are considered moderate risk and require “special controls.” Finally, Class III devices are high-risk devices that typically require a clinical study to demonstrate safety and efficacy. The FDA only “approves” these Class III high risk devices. All other device classifications are not “approved” by the FDA via the pre-market approval (PMA) process.

Where to Start?

Rob Packard is hosting a 2-day workshop  in Amsterdam on 510(k) submissions. Click here for registration information.
Most Class I devices only require that you register your device establishment with the FDA and list the specific device models that are being marketed. Most Class II devices require pre-market notification [i.e., submission of a 510(k)], and receiving “clearance” from the FDA prior to marketing the device. There are always exceptions to this. For example, there are 281 device classifications that are Class II, but these classifications are exempt from 510(k) submissions. There are also 185 device classifications that are Class I, and these classifications require a 510(k) submission. There are also 14 device classifications which are Class III and require a 510(k) submission instead of a PMA. There are even 134 device categories which have not been classified, but these categories require a 510(k).

The philosophy behind requiring pre-market notification [i.e., submission of a 510(k)], rather than pre-market approval (i.e., a PMA), is that lower-risk devices that are substantially equivalent to existing devices on the market should not require approval by the FDA. Instead, these products should only need to demonstrate equivalence. The device you claim equivalence to is called a “predicate” device.

Regulatory Advice Advisable

Most 510(k) submissions are subject to user fees, but pediatric-only products are an exception. If a device is intended for pediatric use only, there is no user fee to encourage the development of new products to treat the smaller pediatric markets with unmet needs. Most companies focus too much on the cost of user fees and the length of the FDA review process, while the cost and time required for your verification and validation testing is much greater. Therefore, it is critical for you to obtain qualified regulatory advice regarding the required testing for your product classification and help in identifying a suitable predicate device. It is also recommended to request a pre-submission meeting with the FDA prior to starting your testing, because it’s better to verify that your testing plan is adequate with the FDA before you spend tens of thousands of dollars and months performing the tests.

The FDA receives FedEx shipments before 10:00 a.m. Eastern time each weekday morning at the Document Mail Center in Silver Spring, MD. The first step is to upload your eCopy into the FDA server. If the automated upload is successful, you receive an automated email around 4:00 p.m. Eastern time on the same day acknowledging receipt of your 510(k) submission. This automated email will also include your 510(k) number. Based upon the review panel indicated, and the specific product classification code, an FDA reviewer will be assigned to your submission and begin the refusal to accept (RTA) checklist.

Two Weeks of FDA Scrutiny

The FDA reviewer assigned to your 510(k) now has two weeks to review your 510(k) submission and complete the RTA checklist. Completing the checklist will only take you a few hours, but each reviewer has a queue of submissions to work through and they did not prepare your submission. The first question in the administrative section of the RTA checklist asks, “Submission contains a table of contents?” An extremely short submission has nearly 200 pages and many submissions have more than 1,000 pages. Therefore, finding the information you need to complete a review in a timely manner can be challenging. A table of contents is essential to efficiently reviewing 510(k) submissions. The second organizational question asks if, “Each section is labeled” and the third question asks if, “All pages of the submission are numbered.” Section labeling and numbering is also essential to efficient review of the submission.

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If the reviewer is unable to find one of the items required on the RTA checklist, you will receive an RTA hold letter. You can receive an RTA hold letter anytime within the first 15 days of the review process, but typically you receive the RTA hold letter on the 14th or 15th day. At busy times of the year, especially October through December, reviewers seem to be tougher in their reviews. However, the reviewer still must complete the RTA checklist. If the reviewer is not as busy, sometimes you will receive an email 2-3 days before the 15-day target indicating that you only have minor corrections. If you submit the minor corrections by email before the 15-day target, the reviewer will accept your correction. This is an unofficial policy, but I have experienced this several times. Below is a link for downloading the RTA Policy, which includes the RTA checklists for all three types of 510(k) submission:
More than 50% of 510(k) submissions are rejected by the RTA screening process the first time, and sometimes the FDA will send a second RTA hold letter if the supplement is still not adequate. Each time you go through the RTA process the FDA review clock restarts at day 0, and the reviewer has 15 days to complete a new RTA screening checklist. In the end you will ultimately receive an acceptance letter. 

Responding to RTA Hold Letter

If you receive an RTA hold letter, then you will need to respond with a supplement submission addressing each item in the hold letter. This supplement is typically identified by S001 and preceded by the K number identified in your RTA hold letter. In general, I recommend not using volumes for responses to an RTA hold letter. I just submit one volume with sequential files matching each of questions in the hold letter. The first document will be a new cover letter indicating that this is a supplement to address each of the questions in the hold letter, while the second document will be your response to the first question. The third document will be your response to the second question, etc. I recommend re-submitting any documents that the reviewer could not identify, and re-submitting any modified documents in their entirety to facilitate a quick review of the supplement. You will also need an eCopy for the supplement.

Over the course of the next 45 days after the RTA process is successfully completed, the substantive review is conducted by a different reviewer with more experience. The experienced reviewer is going to be reviewing your submission and they're going to be looking for is your predicate a legally marketed device? Does your submission meet all the requirements? Have you followed the guidance document, if there is one? Is your test data acceptable? Then the reviewer may come back with additional information requests near the 60-day target.
If the reviewer has additional questions, you'll be asked for a response to each question. In some cases, there are multiple rounds of questions. The instructions in the letter requesting additional information will ask you to address each question and submit a supplement. The reviewer will also ask you to resubmit documents to address each question. If multiple documents are required to address each question, you may want to organize this supplement into volumes and documents, such that each volume addresses a separate question. Alternatively, you can have an appendix volume with the referenced files.
If the reviewer has very few questions, you may receive notification that you have entered the interactive review process. This means that the reviewer believes that the remaining questions are minor and that a decision regarding substantial equivalence can be reached within 30 days.
If a 510(k) submission should have been a De Novo application or a PMA, then you may receive a non-substantial equivalence (NSE) letter. However, you typically will not receive a NSE letter until after a round of additional questions and review of responses. At best, you may get a letter that says they haven’t been able to come to a decision in the expected time frame. They should send a letter to you within 100 days if the reviewer is unable to decide before the 90-day target. 

Patience Required

The FDA counts days only when they are not waiting for your response to a question. Every time they stop the clock, for whatever reason, it makes the whole process seem a lot longer than 100 days. When they say it’s 100 days, it’s more like 120, 130, 140, sometimes even 160 days. If it takes you six months to get 510(k) do not be surprised, because just responding to an RTA hold letter and a request for information typically takes 60-90 days.
Excerpted from Chapters 4 and 7 of "How to Prepare Your 510(k) in 100 Days," 1st edition. Copyright © 2017 by Robert V. Packard.
Rob Packard is a regulatory consultant specializing in 510(k) submissions and helping start-up medical device companies with quality and regulatory requirements. Rob has 25 years experience in the medical device, pharmaceutical and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Rob was a senior manager at several medical device companies—including President/CEO of a laparoscopic imaging company. His quality management system expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for BSI.  The most favorite part of his work is training others.