Q&A: Developing an FDA Regulatory Strategy

R&Q's first webinar of 2020 was the first in a two-part series on bringing your medical device to market in the United States. Part one addressed Class I and Class II devices, while part two (TBA in the spring) will cover Class III devices.

The questions we received related to January's webinar were phenomenal. In this blog post, we share some answers to those questions and hope you find them helpful. Here's a link where you can register for the on-demand webinar (and download the slides) if you have yet to do so.

Q: What are the requirements for Letter to File?

A: 21 CFR 807.81(a)(3) states that a change should be submitted to FDA when a currently marketed device is "about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification:

(i) A change or modification in the device that could significantly affect the safety
or effectiveness of the device, e.g., a significant change or modification in design,
material, chemical composition, energy source, or manufacturing process.

(ii) A major change or modification in the intended use of the device."

We recommend referring to Guidance Document "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and/or "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (), both issued on issued on October 25, 2017, for specific examples and additional information. A risk-based assessment should be used to evaluate the change to determine if the effect of the change is considered significant or modifies the intended use of the device.

Q: Hi, Could you please give example of 510(k) exempt device?

A: There are many class 1 and class 2 devices that are 510(k) exempt. One example is the medical support stocking (21 CFR 880.5780) listed in our presentation! A complete list of 510(k) exempt devices can be found here.

Q: What is the difference between intended use and indication of use?

A: Intended use describes what your device does and encompasses the indications for use. The indications for use describes the patients and conditions the device is used for. For example, total knee replacements could be intended to be used as a total knee replacement in patients with knee joint pain. The indications could then specify painful joint disease due to osteoarthritis, varus/valugus deformity, and post-traumatic loss of joint function. Many times there could be overlap of the intended use and indications for use and both statements could be similar or even the same. It is important to understand the difference and the importance of how to word each statement.

Q: I have a question regarding complying to the latest standard version after getting the 510(k) clearance. Is it necessary to perform any new tests if applicable?

A:FDA does not require conformance to the latest standard version for your testing, so you will not have to reconduct testing with the release of the latest standard. While FDA prefers if manufacturers comply with FDA-recognized standards, conformance is voluntary unless the standard is specifically referenced in a regulation. Please note that if you perform testing that does not conform to an FDA-recognized standards, FDA may ask additional information to justify the differences in test methodology. We recommend searching FDA’s Recognized Consensus Standards database prior to conducting testing to see which FDA-recognized standards are applicable for your device.

Q: If the FDA rejects at RTA, does the clock restart at re-submission?

A: Yes, if FDA rejects your submission during the RTA phase, the submission will be placed on hold and the clock will restart when you re-submit the submission. If placed on hold, you will have a 180 calendar days to address the deficiencies.

Q: Slide 23: "Finish all testing before submitting" ...Historically I've submitted protocols (i.e. sterilization) with completion prior to end of 90-day review period. Can you expand on the comment that this process is "all but extinct?"

A: FDA is becoming more strict on accepting promissory notes to support a 510(k) clearance. The release of the 2016 sterilization and biocompatbility guidance implies that testing should be completed prior to submission (see sources below). While review practices may vary between review divisions and reviewers, submitting a 510(k) without completing all necessary testing carries greater regulatory risk. Individual reviewer decisions should not supercede the recommendations outlined in FDA's officially released Guidance documents. Submitting your regulatory submission without completing the necessary testing runs the risk of being placed on hold and having to complete the required testing during the hold period.

Guidance Documents
Biocompatibility: “Use of International Standard ISO 10993-1, ""Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process""

“Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile”

Q: About 10% of 510(k) submissions have clinical data. We've searched on clinicaltrials.gov to see if clinical tests were done by our predicates (ie. NeuroOne cortical electrodes, PMT cortical electrodes, Ad Tech cortical electrodes) and nothing shows up). Yet we found in a different website that NeuroOne did some pre-clinical study with the Mayo clinic: https://sec.report/Document/0001213900-19-003697/#toc ... Why wasn't the study not found in clinicaltrials.gov? Is it because it was labelled "pre-clinical study?" For the 510(k) submission, does FDA have preference over small animal experiments vs large animal vs pre-clinical trials? Or is it that animal data and pre-clinical trials are a bonus, but not necessary? Because as long as we can show equivalence to predicates out there, animal and/or human data is just the cherry on top? How much importance does FDA place on animal and pre-clinical studies in a 510(k) submission?

A: You are correct that the study may not have been found on clinicaltrials.gov as it is a pre-clinical study. Pre-clinical studies are research conducted in animals prior to moving to conducting clinical trials in humans. As clinicaltrials.gov focuses on research with human volunteers, the pre-clinical study may not show up in your search.

As for FDA's preference for small or large animal studies, it depends on the specificities of your device and the intended used. If you are evaluating the biological response of your device, a small animal model may be acceptable. However, if you are evaluating the biomechanical properties and need a model which will more closely mimic the anatomy of a human subject, then a large animal model may be more appropriate.

Animal data/pre-clinical data is generally used when the risks of your device cannot be completely evaluated using bench testing or through comparison to a predicate. It is important to understand what is required for your device type and the risks associated with it as that will determine the necessity for animal and/or human data.