By Michael Drues, Ph.D., President, Vascular Sciences
Medical device manufacturers make changes to existing products all the time. But how does the manufacturer decide when to handle that change internally, using a letter-to-file, versus notifying the FDA via a special 510(k) or PMA supplement? The choice isn’t always clear, despite the FDA issuing several guidances on this topic over the years.
A letter-to-file and a special 510(k)/PMA supplement are essentially the same thing. Ideally, either choice documents why the change was made, indicates what testing was done to support the change, and shows that the change did not impact the device’s safety, efficacy, or performance.
The real difference between the two is the destination. True to its name, the letter-to-file remains internal, going no further than company filing cabinets. A special 510(k) or a PMA supplement — which one you utilize depends on the regulatory path of the original medical device — goes outside of the company to the FDA.
How To Approach Change Management
Most companies decide right away whether they’ll complete a letter-to-file or a special 510(k)/PMA supplement. In my opinion, that’s a mistake.
First, you need to complete an analysis and conduct the testing to determine whether the planned change could have an impact on the device’s safety, efficacy, or performance. Once that testing and analysis is complete, it becomes a packaging problem: Package the results in a letter-to-file, or send the information to FDA? Again, regardless of which path you choose, the information inside the package is exactly the same.
The decision-making process remains the same, too, whether the change involves modifying device design or the manufacturing process. I advise companies to use regulatory logic, rather than following regulation like a computer mindlessly executing lines of code — step one, do this, step two, do that. Regulatory logic means understanding what the regulation says, but more importantly, asking “Does it make sense?”
I believe that you should start with what makes sense from an engineering and pathophysiological place first, and then consider the regulation afterward. An oft-used adage in medicine states, “The surgery went perfectly, but the patient still died.” The regulatory equivalent of that is “We followed the regulation perfectly — that is, we did all that FDA, Health Canada, or someone else asked us to do — and yet the patient died anyway.” This is a result of following the regulation but not doing what makes sense.
Change Management Case Studies
To better understand how regulatory logic can be applied to change management, let’s look at a few examples I have encountered over the years.
I once worked with a catheter company that wanted to move its logo from one side of the catheter hub to the other. They had noticed that, when a cardiologist used this catheter, the logo typically was facing down, which made the marketing department unhappy.
While this was a seemingly insignificant change, we still went through a bit of analysis, something that can typically be achieved in a few days or, in some cases, a few hours. We found out that moving the logo did impact the way the cardiologist used this particular catheter and, as a result, the change could impact the device’s safety, efficacy, and performance. So, we notified FDA of the change via a special 510(k).
In another case, a clever engineer at an ultrasound company figured out that, if they tweaked the ultrasound frequency a little bit, they could improve the image fidelity. This scenario prompted the question, “How much can you tweak an existing device before you’ve come up with a new device?”
Again, we went through an analysis. From a regulatory perspective, the relatively small frequency change did not affect the labeling requirements — we were not changing the indication for use, nor providing new usage information.
We were able to mitigate the amount of time and effort spent testing by including with our analysis letters from subject matter experts (SMEs) — medical physicists from some top academic institutions attesting to the fact that this change in frequency would not have any negative effect on the patient. We captured this all in a letter to file.
By the way, I’m a big fan of using SME letters whenever I can for a bunch of reasons, not the least of which is that they take very little time and cost very little money to procure. The caveat is, when you ask an SME to write a letter, make it clear that you are not seeking a device testimonial, just expert confirmation that the change to the device does not impact its efficacy or patient safety.
Finally, I worked with a company that had a 510(k)-cleared laparoscopic device on the market. It was made out of an FDA-friendly material, meaning a material that’s been used in other devices and has a proven history.
One of the company engineers figured out that combining this particular FDA-friendly polymer with another FDA-friendly polymer resulted in a material that exhibited better mechanical properties than either of the original polymers alone. This combination of materials had never been used before, and the company came to me with the question, “What constitutes a new material?”
Once again, the regulatory logic analysis process was the same. We demonstrated that the new material would not have an appreciable impact on the safety, efficacy, or performance of the device. Still, I advised the company to be proactive and to submit a special 510(k) to FDA anyway, because we were really in a grey area — if you asked 100 material scientists to evaluate the material, some would probably argue that it was a new material, while others would say it was not. So, we decided to take the high road and send the information to FDA. They asked a couple of questions, but in the end they merely said, “Thanks for letting us know.”
As you can see, choosing between letter-to-file and a special FDA 510(k)/PMA supplement is a business decision, and not so much a regulatory one. The important thing is to conduct the necessary analysis, determine your options, and explore the advantages and disadvantages of each.
Consequences Of Mishandling Change Management
What you really want to avoid is a scenario where you make changes to a device — again, it could be a design change or a manufacturing change — and FDA later arrives at the door asking questions to which you don’t have answers. You don’t want to be in a situation where you have to say, “I’m sorry, we forgot,” or worse, “Oh, you caught us.”
In rare cases, device changes can even draw the attention of a criminal investigation by the FBI. On those occasions, the Department of Justice (DOJ) needs to prove willful intent —it needs to show that the company knowingly made an illegal change. An illegal change, for example, could be a change in the high-level labeling that leads to the marketing of an adulterated, or a misbranded, medical device. And, as with lesser offenses, ignorance is a weak excuse in the eyes of the law.
If the government comes calling, you should be able to pull out your letter-to-file and say, “This is the change we made, this is when we made it, and this is why we made it. This is all of the testing we did to show that the change did not impact safety, efficacy, performance, and so on. And, by the way, here are some letters from subject matter experts saying that they agree with our conclusions.” Ideally, you have done your homework and can also say, “Here are three of our competitors that have done essentially the same thing in similar situations.”
Even if FDA says, “We think you should have come to us with this in advance,” the advantage to this approach is that you have all the necessary information on hand to immediately repackage the letter-to-file into the form of a special 510(k) or PMA supplement. You can tell them, “We’ll send it to you next week.”
Again, the reason why so many companies get in trouble is because they haven’t done the analysis, testing, and documentation. Sometimes, that testing involves a simple literature review or justification based on regulatory logic. What’s important is documenting that justification — make it clear that the company did not forget anything or try to hide anything (i.e., We know what we are doing!). This is a business decision, and your company needs to be confident in its ability to defend itself in any kind of position.
Don’t Be Afraid Of FDA
Admittedly, the analysis/testing process can slightly hinder or impede product development. As a result, I see a small but growing number of companies that impose as a design criterion on their R&D engineers: “Only improve this particular device to the point that we can handle the design or manufacturing change via a letter-to-file, so we do not have to notify the FDA via a special 510(k) or a PMA supplement.” As a former R&D engineer, I’m troubled by that. I don’t see how placing that kind of limitation on R&D engineers is making the world a better place.
Furthermore, I find it unfortunate when companies take the view that FDA is something to be avoided or, in some cases, even feared. My advice to you is simple: Continue to make improvements in the design or the manufacturing processes as you see fit. At the same time, work with the FDA to make that happen; partner with them. Don’t treat them as an obstacle, and certainly don’t treat them as the enemy.
Deciding whether to use a letter-to-file or notifying the FDA via a special 510(k) or PMA supplement is a case-by-case decision — and this will not change, regardless of how much new regulation or guidance is issued. Some companies will be very conservative and, as a matter of policy, notify FDA of all changes. Other companies will be a little more aggressive, and not necessarily notify FDA when they make a change. But whichever path you choose for your device, make sure you are prepared to defend your decision if and when somebody asks about it.