Unboxing Averages: Violations Found in Medical Device Warning Letters | Epstein Becker & Green
Most companies want to avoid FDA warning letters. To help medical device companies identify violations that could lead to a warning letter, this article will dive deep into the specific types of violations often found in warning letters issued by the FDA.
As you probably know, the FDA has a formal process for evaluating inspection records and other documents to determine if issuing a warning letter is appropriate. These procedures are in Chapter 4 of the FDA Regulatory Procedures Manual. Section 4-1-10 of this chapter requires warning letters to include specific legal citations, in addition to plain English explanations of violations. Quotations are meant to refer to both the law and any applicable regulations.
Therefore, to understand the content of warning letters, we must search for both statutory references and regulatory references. Because statutes are deliberately written to be broader in language, references to regulations tend to be more meaningful.
To display the regulatory citations found, I created a word cloud to show the frequency with which different regulatory citations are used in medical device warning letters over the calendar years 2017 to 2021.
If you’re unfamiliar with a word cloud, it’s a way to present words, or in this case references to regulations, in a font size proportional to their frequency.
I recognize that you may not have memorized all the CFR references. Thus, the following table presents exactly the same information, but with the CFR part and CFR title of the regulations included, as well as the specific frequency listed in the “count” column.
The presentation is duller, but the information is probably more useful this way. I cut the Plain English table to six quotes, as I considered five and less to be too idiosyncratic to care about.
The FDA keeps copies of warning letters from the last five years on their website, so currently they have 2017 through 2021. The first tip is to make sure we have all of the device warning letters. It’s not as simple as taking all the warning letters issued by the Center for Devices and Radiological Health. Different FDA offices may issue warning letters, so we need to check, for example, warning letters issued by district field offices that relate to medical devices. By my count, during the relevant period, there were 236 device-focused letters.
Most of the time, the FDA doesn’t just cite the law. To the agency’s credit, they often recite the more specific regulation they believe has been violated. This gives the recipient of the letter a better understanding of what the FDA is objecting to. Of the 236 warning letters, the FDA cited regulations in 180. Subtracting this means that there were 56 warning letters in which the agency only cited a law, not a regulation.
A commonly cited piece of legislation without regulation is Section 501(f)(1)(B) of the Federal Food, Drug, and Cosmetic Act, which defines an adulterated medical device. When a device is marketed without premarket review, the FDA typically cites both adulteration and mislabeling statutory provisions. And in these cases, it’s not uncommon for the FDA to omit any reference to a specific regulation. As a result, it is likely that many of the 56 warning letters that do not contain a reference to a regulation related to failure to obtain pre-marketing approval or clearance. In particular, my analysis found 98 warning letters that included a reference to the adulteration provision. There are other violations besides failure to file a pre-market submission that can lead to tampering, so it’s no surprise the number is higher than 56.
In terms of finding sections of the CFR, those who wrote the warning letters were somewhat inconsistent as to the depth of a reference, i.e. whether it should be to section, sub -paragraph, in paragraph, etc. Accordingly, I have shortened each of the references to the section. I ignored references that were only for parts of the CFR, as they weren’t specific enough to be helpful.
If you read last month’s article, you already know that this data includes statistically anomalous years. The years 2020 and 2021 were COVID years in which the FDA essentially halted routine facility inspections. As a result, the agency was not generating inspection results that would lead to a warning letter. Instead, many warning letters stemmed from issues such as unapproved lab tests for COVID and adulterated personal protective equipment, not based on a specific inspection of FDA facilities.
Immediately before COVID, under the Trump administration, the FDA sent fewer warning letters than under the Obama administration. Indeed, last month I went back 10 years to get results more typical of FDA performance. But I didn’t have that option with warning letters, because the agency archives warning letters as soon as they are five years old. So, in a sense, this data set of warning letters is statistically anomalous when considered in the fuller context of the last decades of FDA warning letters.
But with that historical fact noted, many of the findings are consistent with last month’s analysis of inspection data. Eight of the top 10 violations are violations of good manufacturing practices. This shouldn’t be surprising. The inspection process that focuses on good manufacturing practices (“GMP”) is usually the main pipeline that feeds the warning letter process.
Some of the most frequent citations include design controls, CAPAs, complaint records, production and process controls and, outside of GMPs, failure to report adverse events. None of this should surprise anyone. This has been the standard fare for many years.
Towards the top is 807.81, the regulatory citation the FDA uses when a company should have filed a 510(k) but didn’t. It’s no surprise that the citation was up during years when the application of unapproved COVID tests would have been a high priority, although many of these products fell into the adulterated/mislabeled statutory citations. referenced above.
For me, the most interesting things are not at the very top of the list, but in the middle of the list. Note that the main violations are not so different in terms of frequency compared to the second level. In areas such as purchase controls, non-compliant product and device history files were highly classified. I’ve been doing this for many years and was surprised that device history files were so high on the list. I knew this was a common inspection finding, but I was surprised that so many warning letters listed this as a defect.
Which brings me to one last important point that is honestly not accounted for in this data. Conventional wisdom is that the first or first two items listed in the warning letter are the items that prompted the issuing of the warning letter, but once the agency decides to send a letter, it adds other flaws that may not have been so important. . It’s possible that topics like device history files fall into this category, but I don’t have any data on that. This analysis does not distinguish between regulatory citations listed first in a warning letter and those that follow.
Like the inspection observation data analyzed last month, this data can be considered important inputs into a quality system because it identifies issues that the FDA considers to be among the most important. Next month, I’ll dive into a third piece of quality data, a root-cause analysis of medical device recalls. Along with FDA enforcement data, all of this data points to critical factors that medical device companies have collectively struggled with and perhaps should prioritize remediation.