How to properly document substantial equivalence to multiple predicate devices?

# A Strategic Guide to Using Multiple Predicates in a 510(k) Submission When a single legally marketed device does not exist that is sufficiently similar to a new device, sponsors may need to use a “multiple predicate” or “split predicate” approach in their 510(k) premarket notification. This often occurs with innovative devices that combine features from different existing products—for example, integrating a novel sensor technology from one device with the physical form factor of another. While FDA permits this strategy, it requires a meticulously constructed substantial equivalence (SE) argument to be successful. A robust multiple predicate submission hinges on more than a simple side-by-side comparison. It requires a clear scientific rationale that justifies the choice of each predicate, a detailed analysis of the risks introduced by integrating previously separate features, and a comprehensive testing plan to demonstrate that the final, combined device is as safe and effective as its predecessors. The key is to proactively demonstrate that the combination of cleared components does not raise new questions of safety or effectiveness. ## Key Points * **Designate a Primary Predicate:** The foundation of a multiple predicate argument is selecting a single **primary predicate**. This device should most closely match the new device’s intended use and fundamental scientific technology. Other devices serve as **reference predicates** to support the equivalence of specific features, such as a material, software algorithm, or component. * **The Narrative is Crucial:** The substantial equivalence comparison table must be supported by a detailed narrative. This rationale must explain *why* a multiple predicate approach is necessary and justify the selection of each predicate for its specific role in the comparison. * **Focus on Integration Risks:** The risk analysis must be tailored to address the unique hazards that arise from combining technologies. Focus on the interfaces—mechanical, electrical, software, and material—where new or increased risks may emerge. * **System-Level Testing is Essential:** Verification and validation testing must address the performance of the integrated device as a complete system. It is not sufficient to simply repeat the testing performed on the individual predicate devices; the plan must prove the safety and effectiveness of the final, combined product. * **Proactive FDA Engagement is Key:** Due to the complexity and scrutiny involved, sponsors should strongly consider using the Q-Submission program to gain FDA feedback on their multiple predicate strategy *before* finalizing their testing plan and submitting the 510(k). * **Regulatory Foundation:** The ability to use multiple predicates is based on the principles of substantial equivalence established in FDA regulations, including those found under **21 CFR Part 807**, Subpart E. ## Understanding the Multiple Predicate Approach The 510(k) framework is built on the principle of demonstrating substantial equivalence to a legally marketed "predicate" device. In a straightforward submission, a sponsor compares their new device to one predicate that shares the same intended use and similar technological characteristics. However, when a new device incorporates features from several different cleared devices, no single predicate may be suitable for comparison. In these cases, FDA guidance allows for the use of multiple predicates. This approach involves: 1. **A Primary Predicate:** This is the main device used for comparison. It should have the same intended use as the new device and, ideally, the most similar technological characteristics overall. The primary predicate anchors the SE argument. 2. **Reference Predicate(s):** These are additional legally marketed devices used to demonstrate the equivalence of specific features or characteristics that differ between the new device and the primary predicate. For example, if a new surgical tool uses the same mechanism as the primary predicate but is made from a novel material cleared in a different orthopedic implant, that implant could serve as a reference predicate for the material. FDA reviewers scrutinize these submissions closely because combining cleared components can create a new device with an entirely different risk profile. The burden is on the sponsor to prove that the integration of these features does not introduce new safety or performance concerns. ## Structuring the Substantial Equivalence Argument A clear, logical, and well-supported argument is critical. This requires a methodical approach to both the comparison table and the supporting scientific rationale. ### Step 1: Designating the Primary Predicate The choice of the primary predicate is the most important strategic decision in a multiple predicate submission. It should be the device that provides the strongest basis for the claim of substantial equivalence. Key selection criteria include: * **Intended Use:** The primary predicate MUST have the same intended use as the new device. A difference in intended use will generally lead to a Not Substantially Equivalent (NSE) determination. * **Technological Characteristics:** The primary predicate should share the most critical technological characteristics and principles of operation with the new device. * **Risk Profile:** The overall risk profile of the primary predicate should be comparable to the new device. ### Step 2: Building the Comprehensive SE Comparison Table The comparison table should be expanded to accommodate multiple predicates. A well-structured table makes the argument easy for an FDA reviewer to follow. | Feature | Subject Device | Primary Predicate (e.g., Kxxxxxx) | Reference Predicate (e.g., Kyyyyyy) | Discussion of Differences & Rationale | | ---------------------------- | ------------------------------------ | --------------------------------- | ----------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | **Intended Use** | [Description] | Same | N/A (or Same) | The subject device has the same intended use as the primary predicate. | | **Fundamental Technology** | [Description of Core Mechanism] | Same | Different | The fundamental principle of operation is identical to the primary predicate. | | **Catheter Body Material** | Pebax® XYZ | Pebax® ABC | **Pebax® XYZ** | The material differs from the primary predicate but is identical to that used in the reference predicate, a cleared catheter. Biocompatibility testing was conducted. | | **Sensor Technology** | Optical Reflectance Spectroscopy | N/A (No Sensor) | **Optical Reflectance Spectroscopy** | The sensor technology is identical to that cleared in the reference predicate. System-level performance testing demonstrates it functions safely and effectively. | | **Performance Specifications** | [List of key specifications] | [Data] | [Data] | Performance testing (see Section X) demonstrates that the integrated device meets all specifications and is as safe and effective as the predicate devices. | ### Step 3: Writing the Supporting Narrative The table alone is insufficient. It must be accompanied by a detailed narrative that explains the logic behind the SE strategy. This rationale should: 1. **Explain the Necessity:** Begin by clearly stating why a multiple predicate approach was chosen (i.e., no single predicate exists with the same combination of features). 2. **Justify Each Predicate:** For each predicate (primary and reference), provide a detailed justification for its selection, explaining which specific features it supports in the SE argument. 3. **Address the Combination:** This is the most critical part. The narrative must provide a compelling scientific argument that the *combination* of features is safe. It should directly connect the risks identified from integrating components to the specific performance, biocompatibility, and other testing conducted to mitigate those risks. ## Scenario: A Catheter with an Integrated Optical Sensor To illustrate these principles, consider a hypothetical device: a novel steerable catheter designed for intravascular use that incorporates an optical sensor at its tip to characterize tissue. * **Subject Device:** A steerable catheter with an integrated optical sensor for tissue analysis. * **Primary Predicate:** A legally marketed steerable catheter (Predicate A) with the same intended use (intravascular navigation and diagnosis), dimensions, and base catheter materials. However, it does not have an optical sensor. * **Reference Predicate:** A legally marketed benchtop diagnostic instrument (Predicate B) that uses the exact same optical sensing technology for tissue analysis but is not intended for intravascular use. ### What FDA Will Scrutinize * **The Physical Interface:** How is the sensor, which was previously in a large benchtop unit, miniaturized and safely integrated into the flexible catheter tip? * **Biocompatibility:** Is the final, assembled device with the sensor biocompatible for its intended blood-contacting use? * **Electrical Safety:** What are the risks of electrical leakage or thermal injury from the sensor and its wiring within the patient’s vasculature? * **Sensor Performance:** Does the sensor provide accurate and reliable readings when subjected to the physical stresses, temperature variations, and fluid environment of the bloodstream? * **Sterilization:** Does the chosen sterilization method (e.g., EtO, gamma) negatively impact the sensor's performance or the catheter's integrity? ### Critical Performance Data to Provide The verification and validation plan must be designed to specifically answer these questions. It should go far beyond the testing done for Predicate A and Predicate B individually. * **System-Level Bench Testing:** Mechanical testing (flexibility, tensile strength), sensor accuracy, and durability testing performed on the final, sterilized device. * **Biocompatibility Testing:** Conducted on the complete, finished device per ISO 10993-1, including cytotoxicity, sensitization, and hemocompatibility tests. * **Electrical Safety and EMC Testing:** Testing according to IEC 60601-1 and 60601-1-2 to address risks of shock, burns, and electromagnetic interference. * **Simulated-Use Validation:** Testing the integrated catheter in a validated animal or bench model that simulates the anatomical and physiological conditions of use to confirm the sensor's diagnostic accuracy. * **Sterilization Validation:** Full validation demonstrating that the sterilization cycle is effective without degrading the performance of the catheter or the optical sensor. ## Strategic Considerations and the Role of Q-Submission Using a multiple predicate approach inherently carries more regulatory uncertainty than a traditional 510(k). The sponsor is making a more complex argument that invites greater FDA scrutiny. Because of this, early engagement with FDA through the **Q-Submission program** is a vital strategic tool. A Pre-Submission (Pre-Sub) meeting or written feedback request allows a sponsor to present their proposed predicate strategy and testing plan to the agency for review. This provides an opportunity to: * Confirm that FDA agrees with the choice of the primary and reference predicates. * Gain alignment on the most significant risks posed by the integration of features. * Receive feedback on the sufficiency of the proposed testing plan to address those risks. Obtaining this feedback *before* committing to expensive and time-consuming testing can prevent significant delays and reduce the risk of an NSE determination. ## 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 Managing the complexity of a multiple predicate submission requires exceptional organization. The need to justify each component, link specific risks to mitigation activities, and trace test evidence back to requirements is paramount. Tools like Cruxi can help teams structure their regulatory argument by creating a clear, traceable link between design inputs, risk analysis, verification testing, and the final substantial equivalence narrative. This ensures that every part of the complex argument is supported by objective evidence, making the submission easier to assemble and for regulators to review. *** *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.*