Mastering Responses to FDA 510(k) AI Letters: A Strategic Approach

It takes a significant amount of time, cost, and effort to prepare a premarket notification 510(k) submission.  But that is only the beginning.  After a firm submits a 510(k) to FDA, FDA will request still more information after a first-pass review.  According to the 2^nd Quarter FY2023 MDUFA V Performance Report, FDA issued a request for additional information (AI request) on the first FDA review cycle for 63% to 68% of 510(k)s submitted in FY2018 to FY2022.  In this blog post, we will first briefly outline the procedural steps in the 510(k) review process for medical devices.  We will then present an effective strategy to address FDA’s AI request in a timely manner.

Understanding the Traditional 510(k) Review Timeline

There are three types of Premarket Notification 510(k)s: Traditional, Special, and Abbreviated.  The most common type is the Traditional 510(k), therefore this section summarizes the timeline of the FDA review process for a Traditional 510(k).  However, the strategy of addressing the AI request presented in the next section of this blog post applies to all three types of 510(k)s.  Table 1 below shows the 510(k) submission process based on the MDUFA III Performance Goals.

Table 1. Traditional 510(k) Submission Process.

FDA aims to make the MDUFA Decision (i.e., SE or NSE decision) for 95% of 510(k)s by FDA Day 90 to achieve the performance goals under MDUFA V.  A best-case scenario for a firm would be that FDA does not place the submission on hold and clears it within 90 total calendar days (or less) to reach the SE decision.  However, the reality is usually different.  The 2^nd Quarter FY2023 MDUFA V Performance Report shows that 63% to 68% of 510(k)s submitted over the past five years received an AI request.  As demonstrated by the statistics over the past five years (Table 2), the average number of Total Days (FDA Days + Industry Days) ranged from 127 to 159 calendar days.

Table 2. 510(k) Time to MDUFA IV Decision. Note that days are in calendar days.

When a firm submits a Traditional 510(k), FDA first performs the acceptance review to determine whether a submission is administratively complete, or passes the technical screening for an electronic submission submitted using the eSTAR.  If the submission passes the acceptance review, the firm will receive the first good news from FDA via email that the submission has been accepted for substantive review.  In this case, the FDA clock start date is determined as the date of receiving the submission by the Document Control Center (DCC).  Note that the FDA clock uses calendar days.

FDA then conducts a substantive review.  To achieve the 510(k) performance goals under MDUFA V, FDA aims to make the Substantive Interaction (SI) decision by Day 60 for 95% of 510(k) submissions.  The SI communication could be great news for the firm if FDA notifies that it will continue to resolve any outstanding deficiencies via Interactive Review.  In this case, the FDA’s clock continues to forward without placing the submission on hold.  FDA may issue “real-time” requests by sending an email to the firm with a list of relatively minor questions to resolve.  In such email correspondence(s), FDA may indicate the response due date (usually very tight timelines) and the firm may provide its response by sending an email to the FDA lead reviewer by the indicated response due date.

If FDA issues an AI letter, it could be stressful news for the firm and a very different scenario will play out.  In this case, FDA’s email includes a PDF attachment that lists deficiencies that FDA identified in the submission.  There are two types of deficiencies: major and minor.  If major deficiencies are not adequately resolved, they may preclude a favorable decision on the 510(k).  Minor deficiencies can be resolved in a straightforward manner, but they need to be addressed to meet regulatory requirements or to prevent potential misbranding or adulteration.  When FDA issues an AI request, it places the submission on hold and the FDA clock stops.  The firm has a maximum of 180 calendar days to respond.  The CDRH Portal will highlight the response due date.

The stakes are high.  The firm has a maximum of 180 calendar days to respond, or FDA will treat the 510(k) as terminated.  That deadline seems generous, but it can come quickly if the firm needs to engage with FDA to further clarify the deficiencies, receive feedback on the plan to address the deficiencies, or the firm needs to perform additional testing to adequately respond.  All of these activities must be completed within the 180-day timeframe.  Worse, the firm only has one bite of the apple.  The AI response package must respond completely to all parts of the deficiencies and include all information needed to address the deficiencies; in other words, a firm cannot submit a partially completed response package and plan to submit another AI response package at a later date to address remaining deficiencies.

If the response to an AI request does not successfully address all deficiencies, FDA will issue an order declaring a device not substantially equivalent (NSE) to a legally marketed predicate device (NSE letter).  At this point, if the firm wishes to pursue clearance for its device, it has two options: it may either request supervisory review (i.e., an administrative appeal) under 21 CFR 10.75 or submit a new 510(k) application, which will be reviewed within a new 90-day timeframe.  It is crucial, therefore, to develop a comprehensive response strategy as soon as possible after receiving an AI request.  In the next section of this blog post, we will explore effective approaches to addressing 510(k) AI request to optimize the chances of success.

Comprehensive Analysis of FDA Deficiencies

What is FDA’s guiding principle for generating deficiencies?  The Least Burdensome Provisions, amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) and the 21st Century Cures Act, provide the following principle of generating deficiencies: “Whenever the Secretary requests information to demonstrate that devices with differing technological characteristics are substantially equivalent, the Secretary shall only request information that is necessary to making substantial equivalence determinations. In making such request, the Secretary shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly.” Federal Food, Drug, and Cosmetic Act, Section 513(i)(1)(D)(i).

Per FDA’s guidance documents, Developing and Responding to Deficiencies in Accordance with the Least Burdensome Provisions, each FDA deficiency should include the following four elements: (1) what was submitted, (2) identification of a specific issue or concern, (3) statement of basis for the deficiency, and (4) explicit request for the additional information needed.  We suggest a firm thoroughly review and analyze the AI letter to understand the FDA’s rationale behind the deficiencies and the FDA’s “ask.”

These AI requests often address complicated scientific scenarios in which a submitter has already provided some information, but FDA is not completely satisfied.  Under the guidance, the AI request must summarize the state of play based on the information submitted so far, and then define what would be necessary to resolve the issue.  It is not as easy to formulate this type of request as the firm might think, and as a result, FDA’s AI requests can sometimes seem convoluted.  Not infrequently, a request is lengthy, with multiple subparts.  So the first task is to thoroughly understand each deficiency and map out what will be needed to address it.  This process can require a great deal of time and collaboration as further described below.

Collaborative Planning and Execution

In the AI letter, deficiencies are arranged according to review areas, such as administrative information, 510(k) summary, performance data, engineering performance, biocompatibility, sterilization, software validation, clinical data, and labeling.  An AI letter typically begins with the most significant deficiencies.  There is a wide range of the number of deficiencies−it could be just one major deficiency about one of these review areas.  The AI letter could also present 20 major deficiencies covering multiple review areas and another 30 minor deficiencies.  There is no limit to the number of deficiencies that FDA may generate and include in the AI letter.

Upon receiving the AI letter, appoint a lead person and disseminate the letter among team members for review.  This approach would be particularly helpful if the AI letter covers a wide range of subject matter expertise.  It is typical that a regulatory expert would take the lead.  A spreadsheet may be helpful to track deficiencies, response strategies (e.g., if additional testing is required or justification would suffice), responsible individuals, proposed timelines, and any clarifying questions for FDA.  Team meetings with subject matter experts can be scheduled to discuss response strategies for deficiencies that require extensive clinical, scientific, or engineering input.  If necessary, the firm may engage with third-party laboratories early on to address deficiencies about, for example, but not limited to, biocompatibility, electromagnetic compatibility, or electrical safety and determine timelines for conducting and completing the testing.  When contacting third-party testing laboratories, we suggest discussing the FDA deficiencies with the laboratory personnel so that they understand FDA’s concerns and can generate the data required to address the deficiency as efficiently as possible.  Working with third-party testing laboratories will be effective only if the corresponding deficiency is clearly understood.  If any deficiency is confusing to the firm, we suggest the firm correspond with FDA first to clarify it before planning or conducting any additional testing.

Effective FDA Correspondence Strategy

After a thorough review of the AI letter, the team should consider whether each deficiency is fully understood.  When in doubt, take advantage of FDA’s standard offer of a 10-day call to clarify one or more of the deficiencies.  A list of questions should be prepared and sent to the FDA lead reviewer 48 hours prior to the call.  As this is a 30-minute call, questions should be prioritized in the order of importance to ensure there is time for discussion of key issues.  The 10-day call is intended only to clarify the deficiencies and not to receive FDA’s confirmation on the adequacy of a firm’s plan to address the deficiencies.  It is our experience, however, that some FDA review teams generously offer a quick response to confirm the firm is on the right track in addressing certain deficiencies.  While formal meeting minutes are not mandatory for a 10-day call, it is beneficial to draft minutes and include them in the AI response.

If the scope of the questions submitted for the 10-day call is extensive or if discussion of plans to address the deficiencies is needed, a Submission Issue Request (SIR) pre-submission can be used to seek FDA feedback on proposed approaches to address deficiencies.  If a SIR pre-submission is submitted within 60 days of the AI letter, FDA targets providing meeting or written feedback in 21 days from a request, to the extent resources permit.

Thus, it is beneficial to determine early whether a SIR is needed and to submit as soon as possible within the first 60 days.  If the 60-day mark is missed, FDA may provide meeting or written feedback from a request in 70 days as resources permit.  Note that the method of feedback for a SIR is meeting or written feedback, not both.  However, in our experience, there are some occasions that FDA has offered both written feedback and a meeting for a SIR, and FDA is generally able to respond to follow-up questions interactively via e-mail once the meeting has been held or written feedback provided.  Whether a firm used the 10-day call and/or an SIR, it should include any prior feedback from those interactions with FDA in the AI response and describe how and where in the AI response package the prior feedback was addressed.

Streamlining the AI Response Preparation

The Guidance recommends a response format which entails restating the identified issue and providing one of the following: (1) the requested information or data, (2) an explanation of why the issue does not impact the marketing authorization decision, or (3) alternative information that adequately addresses the issue.

To ensure a comprehensive and timely response within the given 180-day timeframe, it is a good idea to begin drafting responses early on.  This approach not only allows the response to be submitted promptly upon receipt of the last reports or other information, but can also be helpful to identify any gaps in the planned approach and to ensure the team is addressing all aspects of the response.  If the AI response becomes extensive, it can be organized with a table of contents, list of attached files, list of figures, and/or list of tables to facilitate ease of review.  In each response, a firm should include a clear explanation as to how the response addresses the FDA’s concerns.

Tips for Facilitating FDA Review

When providing new test data, a firm should provide a clear narrative description of the goals, protocols, and how the data address FDA’s concerns.  Avoid simply referencing attachments without additional context or descriptions and letting FDA “figure out” the data.  Such responses may lead to reviewer confusion and delay.

When referencing documents within the AI response, cite location within the 510(k) supplement (e.g., Attachment number) and document name or description as appropriate.  When discussing specific information within a referenced document, also include the page number where the specific information may be found.  For labeling documents and the 510(k) summary, FDA often requests both clean and redlined versions.  If a firm provides an editable version of the 510(k) summary to FDA, it may be helpful to facilitate editing and finalizing the 510(k) Summary with FDA.  In the AI response package, hyperlinks can be used to help the reviewer get to the referenced information quickly.  If a response to one deficiency addresses other deficiencies, it is best to refer back to the previous response and avoid redundancy or the potential for inconsistency.

During the recent Regulatory Education for Industry (REdI) Annual Conference, June 6-10, 2022, FDA presented “Tips from a Lead Reviewer” for the presentation titled “Detangling the 510(k) Process.”  In this presentation, FDA suggested the following tips.

Tip #1: Keep in mind that your file will be reviewed by a human

• Keep your file organized
• Must be submitted in English

Tip #2: Check your email often

• Work to get you a decision as soon as possible, within MDUFA deadlines
• Sometimes, this makes it necessary to issue communications during non-business hours
• Don’t forget about your spam folder!

Final Remarks

An FDA AI letter can be lengthy – it is not unusual for AI letters to exceed 10 pages – and therefore challenging to address.  Take a deep breath and address them one by one.  We have had many successful experiences addressing challenging AI requests with the strategic approach discussed here and hope this approach may help your next 510(k) clearance.