When a 483 is issued to a medical device company after an inspection, how should the company respond? What should the response contain? What does FDA look for in a 483 response? And how does the company response impact whether the agency will issue a Warning Letter?

At the virtual 2021 FDA/Xavier MedCon conference, FDA Office of Regulatory Affairs (ORA) Office of Medical Device and Radiological Health Operations (OMDRHO), Division 3 compliance officer Jeff Wooley provided insight into the FDA 483 response review process, including what FDA looks for in a response.

[Related: Redica Systems gives you access to FDA 483 observations. To get a “taste” of this rich data, click here to access a FREE 483 Observation Report.]

He introduced the topic by informing the attendees that “a large part of my job as a compliance officer is to review the investigators’ output—their 483s and their EIRs—and determine what regulatory action, if any, we need to take to move toward compliance. In addition to the investigator’s work, a company’s 483 response is a critical part of this review. It can very much impact the final decision—the final recommendation that I make.” The final decision includes whether a Warning Letter will be issued.

In his presentation, Wooley addressed:

FDA 483 response policy
The Response Letter
Agency review process
Agency response adequacy determination
What documentation to submit with the response
Tips for an effective company response

FDA 483 Response Policy

Federal Register 74 FR 40211 outlines the 15 day period that FDA waits for written responses to a 483. It says if a company submits a written response to the agency within 15 business days of receiving a 483, it will include it as part of any regulatory review that is being conducted. In addition to that, FDA will provide acknowledgment of receipt of the response.

“It is very important that you get this within 15 days,” Wooley stressed. “This is voluntary. You do not have to do this. But it will impact the decision that is being made. One caveat to this policy is that if there is a significant public health risk, I do not have to wait the 15 days to make a recommendation. In the device world, that is very rare.”

Instructions in this area are also provided in the Investigations Operations Manual, the IOM, which is the primary procedure document for FDA investigators. It directs investigators to inform companies during the closeout meeting that an adequate response may impact the determination or the need for additional action.

[Editor Note: For more about the closeout meeting, read The FDA Inspection is Over: What Happens Next?]

“I think these two policies very clearly show you that we want these responses—that we see they are important and they are a major factor in the agency review,” Wooley said. “We are very much asking for these responses.”

In addition to those policies, another document called the Regulatory Procedures Manual, or RPM, is the primary procedural document for compliance officers. “This document gives me a lot of considerations that I have to make when I am reviewing these cases.”

An excerpt from the Warning Letter section of the RPM discusses factors that need to be considered when the agency is considering issuing a Warning Letter. Three considerations that are directly related to 483 responses are listed:

Expectation the firm/persons will take prompt corrective actions
Ongoing or promised corrective actions
Completed corrective actions

The agency does not expect that within the 15-day timeframe a firm can completely, systemically, and comprehensively correct all the observations that the investigator identified.

“But we do want the response to include a plan of action that you come up with. And if there are any activities that you have started, that you have completed, please include those and evidence of those, because I have to consider that as part of my review.”

“These are the things that are going to make an agency compliance officer comfortable that prompt corrective actions are going to be taken,” he explained.

The phrase “prompt corrective actions” means that the agency needs to see timeframes involved. It needs to see that the resources that are going to be necessary are committed to the project and that the management of the company has buy-in on the corrective actions that are being presented.

The Response Letter

Another section of the RPM discusses a very specific letter that FDA can issue: a Response Letter.

“When I review the case as a compliance officer, I may feel a Warning Letter needs to be issued,” Wooley explained. “When a response comes in and it mitigates my concerns to a point that I no longer feel a Warning Letter needs to be issued, I can issue what is called a Response Letter.”

Features of a Response Letter:

The letter does not contain some of the same penalties as a Warning Letter
It is not posted directly to the FDA website
It is not going to be part of the consideration for a certificate to a foreign government
It is not going to affect a government contract
It is a letter saying that essentially the company’s response prevented a Warning Letter from being issued

It contains the same warning statement as in a Warning Letter but essentially will say that if the corrective actions the company has committed to or identified in its response are not followed through, are not completed, or if agency investigators find the same violations at a later date, it may take action without further notice.

Having a section in the RPM on the Response Letter shows this situation happens often enough that it was made part of the agency’s standard operating procedures. Several of these are issued each year across the various FDA inspection programs.

[Related: Click here to access a FREE 483 Observation Report tailored to your team’s needs and see how Redica Systems can save you time.]

The Review Process

Responses are submitted by email. They come to the Director of Compliance Branch (DCB), who will assign them to a compliance officer. Historically, compliance officers did not review every response— they only reviewed responses that were associated with cases recommended for further action. Today they review every response that comes in for any 483.

When a compliance officer reviews a response, the company will get an acknowledgment letter saying the response was received. It is not a substantive review.

Once the compliance officer completes the review, it will be included in whatever communication the agency subsequently sends to the inspected firm. That may be a regulatory action or a letter saying in essence, “the response was good, we will see you next inspection.”

Agency Response Adequacy Determination

Wooley discussed some of the key areas he focuses on when reviewing responses that can have a significant impact on the response adequacy determination. “If these things are not in your response, it could possibly be inadequate,” he commented.

The response needs to address the specific observations that were made by the investigator. For example, if the company was cited for a deficient complaint investigation procedure and was given three examples of complaints identified as not properly investigated, the compliance officer would expect to see that the relevant procedure has been updated and revised appropriately and to see that the three specific examples that were cited have been addressed.

The systemic issues that contributed to the observation and may have impacted product in the field, product in your inventory, other products, other processes, other lines, other quality systems, and subsystems, should be addressed.

“This is by far the most important part of your 483 response,” Wooley pointed out. “This is what is going to weigh the most heavily.”

But we do want the response to include a plan of action that you come up with

Keep in mind that FDA investigators only look at a sampling of records. In the complaint example above, FDA personnel may have looked at 20 complaints, but the firm may have had a thousand complaints that it received over the last few years.

“We would expect to see that you have examined whether there are other complaint investigations that were deficient. We do want to see those. This is a common miss by a lot of companies when they are submitting responses.”
Be sure to include timelines for corrective actions, which need to be realistic and prompt. “I do not want to see that it is going to take two years to update a complaint procedure—that is not reasonable. But I do want to see what the timeframe is and what resources you are devoting to it.”

Submit Corrective Action Evidence

The OMDRHO compliance officer outlined agency expectations for documentation that should accompany a 483 response.

“If you have updated a procedure, if you have redone a validation, I want to see the records that were updated and the procedures that were changed. Please include those so that I can review them to make sure they are adequate and that the work was actually done with data to support these. Include all the supporting data to go with them.”

If the firm did a retrospective complaint review, FDA is interested in how many complaints were examined, how many were deficient, and how many were resolved. If the company completed a new process validation, provide evidence supporting that the validation was correctly done and complete.

“I will also ask for timeframes and plans for recurring progress updates. Those will not affect the adequacy decision,” Wooley explained.

The response needs to address the specific observations that were made by the investigator

“I do not expect all these corrective actions to be completed within that first 15-day response, but I do want to see how often you are going to update me with the actions as you progress. And again, this needs to be reasonable. Most of the time, this is a month to begin with and then most firms will extend it out as we kind of get further down the road and we are just waiting on some bigger hanging issues that are waiting to be resolved.”

It is important to address all discussion items, the compliance officer stressed, noting that failure to do so is another common miss by a lot of firms. FDA does not include certain deficiencies on a 483, he said —for example, 510(k) deficiencies, PMA deficiencies, labeling deficiencies, or certain recall deficiencies— but the investigator will make those discussion items.

“These can often be some of the most significant violations that are identified during the inspection. Make sure you are including responses to discussion items so that we can make sure those are included.”

Five Tips for Effective 483 Responses

Following are Wooley’s Tips for Effective Responses. “These are just ideas to help make sure that I completely and fully understand the response that you have submitted,” he said.

“Include a narrative description of activities. A lot of firms will just submit a handful of procedures and records and expect me to understand and know exactly what was changed and why it was changed. If you do that, it is going to take me a very long time to review because I have to go line by line against what was collected during the inspection to figure that out and I am going to end up having to make a lot of assumptions on what something means and why it was implemented. So narrative descriptions that explain to me what was changed and why it was changed are very, very helpful.
“Please do not bury substantial actions or information that you need an FDA response to, or that are going to require some additional FDA action. For example, if you conduct a recall as part of your corrective actions, please do not put it on page 642 of your response in six-point font. This is a major action that I need to talk with my recall coordinators about. I may need to have conversations with CDRH. Please put that upfront and early to make sure that I see it quickly and soon and can act on it, quickly and soon.
“If you are ceasing production on a certain product, if you are shutting down a facility, if you are going to submit a new 510(k) or a PMA, these are all very important things that I need to know sooner rather than later. So please do not hide them in your response.
“It is very helpful for firms to assemble deliverable tables—a table or graphical representation that identifies the observation each is in response to, the corrective actions that are being taken, and the status of the corrective actions, along with the timeframe. This is a nice, quick reference that helps me quickly update people in the agency, particularly people in the agency that have not viewed the entirety of this response. It helps me explain what is going on including corrective actions quickly and in a nice way.
“All our responses are coming in electronic form. Keep that in mind and try to make them navigable in an electronic format—for example, using bookmarks and links. If you have a very large response, please bookmark the PDF. Links to pages and sections in the document are useful so that I can quickly navigate and identify certain records. Please do not just send a one-thousand-page PDF in which I cannot tell where one document ends and another begins. That is very hard to review and I may misunderstand something in your response.”