The 510(k) submission process is often used for Class II devices to obtain clearance from the U.S. Food and Drug Administration (FDA), while the premarket approval (PMA) route is usually chosen for Class III devices. The 510(k) review process determines substantial equivalence (SE) with a predicate device. That device needs to be at least as safe and effective as the predicate to claim SE with that device. The device under 510(k) review needs to show the following to claim SE:

• Same intended use as the predicate device, and
• The same technological characteristics as the predicate device, or
• Different technological characteristics and information/testing, suggesting the device is as safe and effective as the predicate and different questions about safety and efficacy than the predicate device are not raised.

Failure to meet these criteria leads to a non-substantial equivalence (NSE) determination.

510(k) Review Process
The FDA 510(k) review process can broadly be divided into two steps—acceptance review and substantive review. With acceptance review, by day 15 (day 1 is the day the FDA receives the application), the FDA informs the applicant whether the application is accepted for substantive review or placed on Refuse to Accept (RTA) hold. Per FDA data, in 2018, approximately 30 percent 510(k)s were placed on an RTA hold. With substantive review, by day 60, the application goes through an interactive review or an additional information request is sent. In 2018, 63 percent of 510(k) applications in the substantive review phase resulted in an additional information request; 13 percent were determined to be NSE.

FDA data depicts the following types of common additional information requests:

• Inadequate device description
• Discrepancies throughout submission (discrepancies in this category are most often related to device description or indications for use)
• Problems with indications for use
• Failure to follow or otherwise address current guidance document(s) or recognized standards
• Performance testing required for certain device types is completely missing (i.e., no performance data provided at all)
• Clinical data required for certain device types is completely missing (i.e., no clinical data provided at all)

Common Mistakes to Avoid
1. RTA Letter—The purpose of acceptance review at initial stage is to check if the 510(k) application is administratively complete. It is highly recommended to review the acceptance checklist provided in guidance document “Refuse to Accept Policy for 510(k)s.” To ensure successful acceptance review, each company is suggested to follow elements in the tables from the guidance.

• Preliminary Questions Table: Though this checklist is intended for the reviewer to make initial determination, it is highly recommended to answer these questions informally before submitting the application to FDA.
• Organizational Elements Table: These elements help organizing in a manner that enables easy identification of the information in the 510(k) application.
• Elements of a Complete Submission (RTA Items) Table: Firms should pay closer attention to elements listed in this table as these elements are critical in not receiving an RTA letter.

2. Inadequate Device Description—Device description is mandatory in a 510(k) application. It is suggested to add a brief description and technical specifications in this section. All device models and accessories should be included, along with pictures, dimensions, drawings, and tolerances for each component. Missing an important model or accessory may lead to confusion and additional questions. Inappropriate technical specifications may lead to misconception and request for additional testing.

3. Inconsistent Information Throughout the Submission—If a company decides to do a 510(k) submission to add an additional model, it is important that applicable sections such as cover letter, device description, labeling, substantial equivalence discussion, and performance-related sections are aligned with the actual change. Inconsistency may lead to administrative delays and, in worst case, request for additional testing.

Similarly, inconsistency in indication for use in various sections of the 510(k) may cause issues. The indication for use statement is very important in the SE determination.

Inconsistencies in various sections could easily be avoided by careful review of the submission before it is submitted to the FDA. It is always a good idea to have an extra set of eyes take a look at various sections to avoid such mistakes.

4. Different Intended Use than the Predicate Device—To get a SE determination, the device must have the same intended use as the predicate. This is important because a different intended use may lead to different safety and efficacy issues. In such a case, 510(k) may not be an appropriate pathway for product clearance. It should be noted that differences in the indication for use between a predicate and a device under 510(k) review may not necessarily result in different intended use. Companies should put additional efforts to clearly show differences in the indication for use have not resulted in different intended use. The guidance “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]” should be referenced to gain clarity on the intended use related questions.

5. Inadequate/Missing Testing Information—It is important to understand applicable testing for any particular device. Based on the type of device, electrical safety, electromagnetic compatibility, biocompatibility, software validation, sterilization, and/or usability testing may be required to claim safety and efficacy of a device. Oftentimes, companies underestimate the amount of testing required or try to provide rationale to not conduct a particular testing.

For example, companies may rely on a similar device’s biocompatibility data to claim biocompatibility for their product. This approach may be acceptable in some cases but manufacturing process differences may warrant separate biocompatibility testing on the device under 510(k) review. Such additional testing may take several weeks. If FDA requests additional testing during the 510(k) review, it will add significant time to the final clearance. Appropriate teams should give thorough consideration to current FDA guidance, product design, and the risk management process to make a determination about the amount of testing required.

In addition, it is important to understand the difference between a Traditional 510(k) and a Special 510(k). All testing data must be included in the Traditional 510(k).

6. Failure to Follow or Otherwise Address Current Guidance Document(s) or Recognized Standards—As previously discussed, ensure testing is conducted to show compliance with the latest recognized standards. There may be significant changes in the latest version of the standard compared to previous versions. This may result in additional questions about safety and efficacy if a device is not tested with the latest version of the standard.

Referring to the latest guidance helps with understanding FDA’s expectation or recommendations. This also makes the FDA review process easier as the submission is written in an easily understandable format.

7. NSE Determination—The ultimate goal of the 510(k) process is to determine SE with a predicate device. When additional information is requested by the FDA during the substantive review phase, companies should carefully review each request and provide a scientifically sound response. Failure to provide the requested data/response may result in an NSE determination. It is highly recommended to consult and collaborate with FDA to understand expectations at this phase.

8. Submitting Application at the Correct Address—This is easily avoidable human error. Always refer to the FDA website for the correct address to submit an application.

9. Including Hard Copy and eCopy per Latest FDA Recommendation—The FDA has specific requirements for the number of hard copies and eCopies that need to be submitted for a 510(k) application. Currently, one of each is required, but don’t make any assumptions. Refer to the FDA website before submitting.

10. eCopy-Related Issues—The submission must meet eCopy technical standards. Refer to the eCopy guidance to prepare an eCopy of the application. Further, PDF naming convention and file size recommendation must be followed to avoid an eCopy hold letter. Although use of the eSubmitter eCopies tool is voluntary, this tool helps to validate eCopy per FDA recommendations.

11. Submitting Information to Reviewer—After receiving the initial hold letter from the FDA (e.g., RTA hold, eCopy hold), companies often make a mistake while submitting information to the reviewer. Check the email received from the FDA or appropriate guidance about where to send a response to the hold letter.

12. Traditional 510(k) vs. Special 510(k)—Companies can make a mistake in categorizing an application as a Traditional 510(k) or a Special 510(k). The major difference between them is the time required to review the application by FDA. A Special 510(k) takes 30 calendar days while the Traditional 510(k) takes 90 calendar days. The FDA has requested companies to convert a Special 510(k) to a Traditional 510(k), which ends up wasting time due to the conversion process.

Per the FDA, a Special 510(k) may be appropriate when:

• The proposed change is submitted by the manufacturer legally authorized to market the existing device;
• Performance data are unnecessary, or if performance data are necessary, well-established methods are available to evaluate the change; and
• All performance data necessary to support substantial equivalence can be reviewed in a summary or risk analysis format.

To avoid such a mistake, do thorough research on the FDA database to identify if a similar change was submitted as a Special 510(k) or Traditional 510(k). Refer to guidance documents from the FDA. If you are still in doubt, enlist help from regulatory consultants. Use a risk-based approach. If still in doubt, it is recommended to take a conservative approach and submit a Traditional 510(k).

13. Nature of the Device—Some devices may raise specific questions due to the unique nature of the device. Certain technological areas such as artificial intelligence and cybersecurity are relatively new. The FDA has collaborated with industry to develop guidance documents in these areas.

In such cases, a meeting with FDA before the 510(k) submission is highly recommended. Refer to the FDA guidance document if feedback and a meeting with FDA before a 510(k) submission is needed.

Conclusion
RTA letters from FDA can easily be avoided by careful review of the submission and following FDA guidance documents. An additional information request as part of the substantive review process can be reduced with clear and concise writing. This is often a combination of science, art, and experience. It is highly recommended to employ the help of experienced regulatory affairs consultants in writing a 510(k) application to avoid costly mistakes. Stay up to date in terms of applicable regulations, standards, and guidance documents to increase the chances of a successful submission. 

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Samradni Patil is a freelance FDA submissions consultant and regulatory writer at Kolabtree, the freelance platform for scientists.