What is the difference between a 510k RTA hold and an AI request?

## RTA Hold vs. AI Request: A Deep Dive into FDA 510(k) Review Holds When a medical device sponsor submits a 510(k) premarket notification, receiving a communication from the FDA that places the submission on hold can be a source of significant anxiety. However, not all holds are created equal. Understanding the fundamental difference between a **Refuse to Accept (RTA) hold** and an **Additional Information (AI) request** is critical for developing an effective response strategy and managing regulatory timelines. An RTA hold is an administrative gatekeeping step that occurs within the first 15 calendar days of submission. Its purpose is not to evaluate the scientific merit of the device but to determine if the submission is administratively complete and formatted correctly for a substantive review to begin. In contrast, an AI request is issued during the substantive review (after a submission has passed the RTA check) when the FDA reviewer requires more data, clarification, or scientific justification to make a substantial equivalence determination. These two holds represent different stages of the review process, focus on entirely different aspects of the submission, and demand distinct response strategies. ### Key Points * **Timing is Everything:** An RTA hold occurs at the very beginning of the process (within 15 days) before the substantive review clock starts. An AI request happens during the substantive review, after the 90-day review clock has already begun. * **Focus of Review:** RTA is an administrative checklist review focusing on the *presence* and *organization* of required elements (e.g., proper formatting, inclusion of all necessary sections). AI is a scientific review focusing on the *content and quality* of the data and arguments presented. * **Impact on Review Clock:** An RTA hold prevents the 90-day FDA review clock from ever starting. The submission is not considered officially "accepted for review." An AI request pauses the 90-day review clock until the sponsor provides a complete response. * **Nature of Deficiencies:** RTA deficiencies are typically administrative, such as a missing form, an incorrectly formatted eCopy, or the absence of a required section. AI deficiencies are substantive, such as a request for additional performance data, clarification on a risk analysis, or questions about the chosen predicate. * **Response Strategy:** Responding to an RTA involves correcting the administrative checklist items and resubmitting the entire 510(k). Responding to an AI request involves generating and submitting new data, analysis, or scientific rationale to directly answer the reviewer's questions. --- ### Understanding the RTA Hold: The Administrative Gatekeeper The RTA policy is designed to enhance the efficiency of the 510(k) review process. By ensuring a submission is administratively complete and well-organized from the start, the FDA can allocate its scientific review resources more effectively. Think of the RTA phase as a preliminary screening to ensure all the necessary paperwork is in order before the real evaluation begins. #### What Does the RTA Review Focus On? The RTA review is guided by a publicly available FDA checklist. It is a systematic, objective assessment of completeness, not a subjective evaluation of the science. Common elements scrutinized during this phase include: * **Administrative Elements:** * Verification of user fee payment. * A signed and dated cover letter. * A complete FDA Form 3514 (510(k) Cover Sheet). * A valid eCopy of the submission that meets FDA's technical standards. * **Core Submission Content (Presence, not Quality):** * **Indications for Use (IFU) Statement:** The submission must contain a clear IFU page (FDA Form 3881). * **Device Description:** A section describing the device's components, materials, and principles of operation must be present. * **Substantial Equivalence (SE) Comparison:** A summary comparison table contrasting the proposed device with a legally marketed predicate device must be included. * **Proposed Labeling:** Draft labeling, including instructions for use, must be part of the submission. * **Performance Data Summaries:** The submission must contain summaries of all performance testing (e.g., non-clinical bench, biocompatibility, software validation). The RTA review verifies that these sections exist, not that the data within them is adequate. * **Relevant Guidance Documentation:** If the device falls under a specific FDA guidance document (e.g., cybersecurity), the RTA review will check that the submission includes the documentation recommended by that guidance. #### Impact on the 510(k) Review Clock This is the most critical distinction. If a 510(k) submission receives an RTA hold, the **90-day review clock does not start**. The FDA considers the submission incomplete and will not proceed with a substantive review. The sponsor has up to **180 calendar days** to address the deficiencies outlined in the RTA checklist and resubmit the entire 510(k) package. Only after the revised submission is received and passes the RTA check will it be considered "accepted," and only then does the 90-day review clock officially begin. --- ### Understanding the AI Request: The Substantive Review An AI request signifies that your submission has successfully passed the administrative RTA screening and is now undergoing a deep scientific and regulatory evaluation. During this phase, an FDA reviewer is meticulously assessing the data, testing methodologies, and scientific rationale supporting the claim of substantial equivalence. An AI request is a standard, interactive part of this process. #### Common Triggers for an AI Request AI requests are highly specific to the device and the content of the submission. For a device like a **digital diagnostic imaging system**, an AI request could be prompted by numerous substantive issues: * **Performance Data Questions:** The reviewer may find the bench testing protocol insufficient to support the device's performance claims or may question the statistical analysis of the results. They might ask for raw data or a re-analysis. * **Predicate Comparison Issues:** The reviewer may identify technological differences between the new device and the predicate that raise new questions of safety or effectiveness. They may ask for additional testing to address these differences. * **Cybersecurity Concerns:** As per FDA guidance documents like "Cybersecurity in Medical Devices," the reviewer might request a more detailed threat model, additional penetration testing results, or clarification on the plan for managing postmarket vulnerabilities. * **Biocompatibility or Sterilization:** If the device has patient-contacting components, the reviewer might question the rationale for material selection or request clarification on the sterilization validation methods. * **Labeling Deficiencies:** The reviewer may find the proposed Instructions for Use unclear, incomplete, or lacking adequate warnings and precautions. #### Impact on the 510(k) Review Clock When the FDA issues an AI request, the **90-day review clock is placed on hold**. The "time on hold" does not count toward the FDA's 90-day review goal. The clock remains paused until the FDA receives a complete response from the sponsor. Sponsors generally have up to **180 calendar days** to respond to an AI request. Upon receiving the response, the review clock resumes where it left off. #### Best Practices for Responding to an AI Request A well-crafted AI response is crucial for a successful 510(k) outcome. The goal is to provide a clear, complete, and compelling answer to every question raised by the FDA. 1. **Deconstruct Every Question:** Carefully read and understand the precise nature of each FDA question. Do not make assumptions. If there is any ambiguity, it is appropriate to contact the FDA reviewer to request a brief teleconference for clarification. 2. **Create a "Question-and-Answer" Format:** Structure your response document by restating each of the FDA's questions verbatim. Follow each question with your comprehensive, direct response. This makes it easy for the reviewer to confirm that every item has been addressed. 3. **Provide Data, Not Just Narrative:** Support your answers with data, testing reports, updated risk analyses, and revised documentation. Clearly label all new information and provide summaries that explain how the new information resolves the FDA's concern. 4. **Reference and Link:** In your response, clearly reference the location of the new or updated information within the submission (e.g., "Please see the updated Software Validation Report in Section 16.2"). 5. **Perform a Final Review:** Before submitting, conduct a thorough internal review to ensure the response is complete, accurate, and directly answers all parts of the AI request. A partial response may lead to further questions or a negative decision. --- ### ## Scenario: Navigating an RTA and AI for a Digital Imaging SaMD To illustrate the difference, consider a sponsor submitting a 510(k) for a new Class II Software as a Medical Device (SaMD). The software uses an AI algorithm to assist radiologists in identifying potential bone fractures on X-ray images. #### Part 1: The RTA Hold The sponsor submits their 510(k). On day 12, they receive an RTA hold notice. * **RTA Deficiencies:** The FDA's RTA checklist identifies two key issues: 1. The submission lacks a dedicated section addressing the cybersecurity recommendations outlined in FDA's guidance, which is expected for a connected software device. 2. The Substantial Equivalence comparison table is missing key technical specifications for the predicate device, making a side-by-side comparison impossible. * **The Problem:** These are administrative completeness issues. The FDA has not yet evaluated the software's algorithm or its clinical performance. The 90-day review clock has not started. * **Sponsor's Response:** The sponsor's regulatory team spends two weeks compiling the required cybersecurity documentation and updating the comparison table with the missing predicate information. They then resubmit the *entire*, corrected 510(k) package. The new submission passes the RTA check, is formally accepted, and the 90-day review clock begins. #### Part 2: The AI Request On day 65 of the review, the sponsor receives an AI request. * **FDA's Questions:** The substantive review has generated questions about the science: 1. The reviewer requests the full, de-identified dataset used to train and validate the AI algorithm to independently verify the sponsor's performance claims. 2. The reviewer asks for a more detailed description of the sponsor's plan for managing algorithm drift and future software updates post-clearance. * **The Problem:** These are substantive, scientific questions. The reviewer needs more information to be confident in the device's safety and effectiveness relative to the predicate. The 90-day review clock is now paused at day 65. * **Sponsor's Response:** The sponsor's technical and regulatory teams collaborate to prepare a response. They provide the requested dataset along with a memo explaining the data structure. They also write a detailed Standard Operating Procedure for their postmarket software maintenance plan. They submit this new information as their formal AI response. The FDA receives it, and the review clock resumes. --- ### Strategic Considerations and the Role of Q-Submission Proactive engagement with the FDA can significantly reduce the risk of both RTA holds and major AI requests. The Q-Submission program is the most valuable tool for this. By requesting a Pre-Submission (Pre-Sub) meeting, sponsors can: * **Prevent RTA Holds:** Discuss the overall structure and content of the planned 510(k), confirming requirements for specific documentation like cybersecurity or human factors testing. This ensures the final submission package is complete and aligned with FDA expectations from day one. * **Mitigate AI Requests:** Gain early feedback on the proposed testing strategy, predicate device rationale, and any novel features of the device. Addressing potential scientific concerns *before* submitting the 510(k) can prevent major AI requests and lead to a smoother, more predictable review cycle. ### Key FDA References - FDA Guidance: general 510(k) Program guidance on evaluating substantial equivalence. - FDA Guidance: Q-Submission Program – process for requesting feedback and meetings for medical device submissions. - 21 CFR Part 807, Subpart E – Premarket Notification Procedures (overall framework for 510(k) submissions). ## How tools like Cruxi can help Navigating the complexities of a 510(k) submission requires meticulous organization. An RTA hold, in particular, often stems from avoidable administrative errors. Tools like Cruxi can help teams manage their regulatory submissions by providing structured templates, collaborative checklists, and a centralized platform for all documentation. By ensuring that every required section is accounted for and formatted correctly before submission, teams can significantly reduce the risk of an RTA hold and build a more robust, review-ready package from the start. *** *This article is for general educational purposes only and is not legal, medical, or regulatory advice. For device-specific questions, sponsors should consult qualified experts and consider engaging FDA via the Q-Submission program.* --- *This answer was AI-assisted and reviewed for accuracy by Lo H. Khamis.*