Device experts offer tips on handling warning letter, 483 responses

COLUMBUS, OH – One of the most common technical questions posed to US Food and Drug Administration (FDA) officials by manufacturers is the agency’s expectation for responding to a Form 483 or warning letter.

Many people believe that a company is required to respond to a Form 483 within 15 calendar days, but this isn’t true, Gina Brackett, division 1 director, compliance branch at the Office of Medical Device and Radiological Health Operations (OMDRHO), Office of Regulatory Affairs (ORA) within FDA, told attendees during the 2024 MedCon conference, sponsored by the AFDO/RAPS Healthcare Products Collaborative and FDA.

“First of all, you’re not required to respond to an FDA 483,” Brackett said. The 15 calendar day deadline for response, she explained, is if the agency is considering a warning letter. “[I]f you want your response included in that warning letter, then you need to respond in the 15 calendar days.”

“The warning letter requires it, the 483 does not,” she reiterated.

Brackett said the reason this 15-day response requirement came about was because FDA would receive responses just before they were ready to issue a warning letter. However, they do look at responses that come from companies after the 15-day response time, she noted.

Warning letter response

Manufacturers should be forthcoming in their response to a warning letter, Brackett said.

“I will tell you, when you respond, don't promise everything’s going to be fixed next week. That doesn't happen,” she said. “We understand that you're not going to have … a protocol written before you respond sometimes.”

Jessica Zeller, vice president, quality, regulatory, environmental, and public affairs counsel at Edwards Lifesciences, echoed the idea of not overpromising in a company’s response.

“You have to be specific and comprehensive, but if you promise you're going to do something in 15 days, and on day 18, the agency says, ‘Okay, let us see it,’ and you are 60 days out still, you've continued to erode any credibility you may have still had by that point,” she said.

Being “as realistic as possible” with deadlines may be painful, but it’s important to actually hit the deadlines you give the agency, she explained.

“Once you've told the agency you're going to do it that way, don't miss them,” Zeller said. “[Y]ou better have a really good explanation, because … the trust level in the discussions that you're going to have to have on the go forward, whether it turns into a warning letter or not, or turns into enforcement or not, that trust level is all you got left at that point. So don't make it worse.”

Outlining a timeframe with a comprehensive plan for corrective action is another important aspect of a company’s response, Brackett said. In the case of Medical Device Reporting (MDR) failures, companies may say they’re going to perform a 2-year retrospective review of complaints, but not provide a timeframe. Sometimes companies may need to review MDR reportability for more than one product. However, it’s important to be transparent with FDA on the scope of the issue and the timeframe, she explained.

From the industry perspective, some companies are choosing to voluntarily respond within 15 days, Monica Wilkins, VP Regulatory and Quality at Abbott, told attendees.

“One of the things that we tell our divisions, and our subsidiaries, is that they have to be thorough,” she said. “You have to provide plans because we also agree there are some things you cannot fix in 15 days. You have to come in with a plan, be thorough and make sure you're understanding your root causes and that you're addressing the root causes.”

Some corrective actions can last years, she pointed out, and the agency has to accept the company’s plan. There will be periodic updates, and occasionally meetings with the agency may be warranted if there were extensive observations that would necessitate a meeting to “go over your plan and make sure that you covered all of the elements that were the agency's concern.”

Aaron Dunbar, vice president quality systems and post market at Boston Scientific, said companies should not simply state the root cause, but follow their processes for identifying the root cause.

“Fight the urge to get that within 15 days. Use your processes. That’s why you have them, to make sure that you’re following what you should be doing. If you’re reacting, you make mistakes,” he said.

Companies should also look at their containment actions, Dunbar noted. “You have that process validation issue. If you have something that you need to further investigate, what are you going to do to stop it right now? That’s one of the common things that I see people forgetting as well,” he said.

Device experts offer tips on handling warning letter, 483 responses

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