How to determine substantial equivalence with multiple predicate devices?

# How to Demonstrate Substantial Equivalence Using Multiple Predicate Devices When developing a new medical device, it is common for innovation to come from combining existing, proven technologies. A sponsor might incorporate a novel sensor from one legally marketed device with a unique delivery system from another. This raises a critical question for the 510(k) pathway: How can a sponsor demonstrate substantial equivalence when the new device’s features are drawn from multiple predicate devices? This approach, often called a "multiple predicate" or "reference device" strategy, is permissible but requires a carefully constructed scientific rationale and a clear submission structure. The primary challenge is to prove that the combination of features does not create a "new worst-case scenario" or raise new questions of safety and effectiveness. The goal is to present a logical, evidence-based argument that the new device is at least as safe and effective as its predicates. This involves selecting a single primary predicate, leveraging secondary predicates as "reference devices" for specific features, and conducting robust testing that addresses the risks of technological integration. ### Key Points * **Select a Single Primary Predicate:** A 510(k) submission must be based on a comparison to one primary predicate device. This device should have the same intended use as the new device and similar technological characteristics. * **Use Secondary Predicates as "Reference Devices":** Other legally marketed devices can be used as "reference devices" to support the substantial equivalence of specific features (e.g., a material, a sensor, a software algorithm) that differ from the primary predicate. * **Avoid "Cherry-Picking":** The selection of predicates and reference devices must be driven by a sound scientific rationale, not by convenience. Sponsors must justify why the combination is appropriate and does not introduce new risks. The final integrated device must be evaluated as a whole. * **Focus on Integration Risks:** The risk analysis and testing plan must go beyond component-level comparisons. It is critical to conduct comprehensive system-level testing to evaluate how the combined features interact and to identify any new or increased hazards resulting from their integration. * **Develop a Clear and Logical Comparison:** The device description and substantial equivalence comparison sections must be exceptionally clear. Use a main comparison table for the primary predicate and supplemental tables or narratives to clearly explain how reference devices support specific features. * **Leverage the Q-Submission Program:** For any device using a multiple predicate strategy, early engagement with the FDA via the Q-Submission program is highly recommended to de-risk the submission by gaining alignment on the choice of predicates, the comparison strategy, and the proposed testing plan. --- ## Understanding the Multiple Predicate Strategy Under 21 CFR Part 807, a device is substantially equivalent if, in comparison to a predicate, it has the same intended use and the same technological characteristics, or has different technological characteristics but the submitted information demonstrates that the device is as safe and effective as a legally marketed device and does not raise different questions of safety and effectiveness. When a new device combines features from multiple sources, the sponsor must still select a **single primary predicate** that represents the best overall fit, primarily based on intended use. Other devices are then used as **reference devices** to support the equivalence of specific, distinct features. ### The Pitfall of "Cherry-Picking" FDA reviewers are trained to identify "cherry-picking," which occurs when a sponsor selectively combines the most favorable features from multiple predicates without a valid scientific justification for the combination. For example, claiming the intended use from Predicate A, a performance specification from Predicate B, and a material from Predicate C simply because each is the easiest to meet is not a valid strategy. To avoid this, the sponsor must present a cohesive argument demonstrating that the integrated device, as a whole, is substantially equivalent to the primary predicate. The use of reference devices is to show that a specific *different* technology in the new device is already well-understood and has a history of safe and effective use in the market. ## Structuring the 510(k) Submission and Comparison Clarity is paramount when using a multiple predicate approach. The reviewer must be able to easily follow the logic connecting the new device to the primary predicate and each reference device. ### Step 1: The Main Comparison Table The submission should lead with a comprehensive comparison table that directly compares the new device to the **primary predicate only**. This table should cover: * Intended Use and Indications for Use * Technological Characteristics (materials, design, energy source, etc.) * Principles of Operation * Performance Specifications * Patient-Contacting Materials and Biocompatibility ### Step 2: Supplemental Comparisons for Reference Devices For each feature of the new device that is not present in the primary predicate but is supported by a reference device, create a separate, focused comparison. This can be a smaller table or a detailed narrative section. **Example:** Imagine an imaging catheter (New Device) that uses the same steering mechanism as its primary predicate (Predicate A) but incorporates a new type of sensor found in a different marketed device (Reference Device B). * **Main Table:** Compares the New Device to Predicate A across all features. In the "Sensor Technology" row, it would state that the technologies are different. * **Supplemental Section:** A dedicated section titled "Comparison of Sensor Technology to Reference Device B" would follow. This section would include a small table or narrative comparing *only the sensor characteristics* of the New Device and Reference Device B, demonstrating their similarities. ### Step 3: The Scientific Rationale Narrative This is a critical section that ties everything together. It should explicitly explain: 1. **Why the primary predicate was chosen.** 2. **Why reference devices are necessary** to support specific technological differences. 3. **Why the combination of features is safe and effective.** This should directly address why the integration does not raise new safety or effectiveness questions. For example, explain why the sensor from Device B does not negatively impact the steering mechanism from Device A. ## Testing and Risk Analysis for Integrated Systems While component-level testing is necessary, it is not sufficient. The FDA's primary concern will be the potential for negative interactions between the combined components. ### System-Level Integration Testing The testing plan must be designed to evaluate the fully integrated device. Key areas include: * **Functional Performance:** Does the device meet all performance specifications when all components are operating simultaneously? (e.g., Does activating the sensor affect the catheter's steering precision?) * **Electrical Safety and EMC:** The integrated system must be tested for compliance with relevant standards (e.g., IEC 60601-1 series). The risk of electrical interference between components must be assessed. * **Biocompatibility:** The entire patient-contacting device, in its final finished form, must be evaluated for biocompatibility. * **Cybersecurity:** If the device includes software or wireless components, the integration of different technologies can create new cybersecurity vulnerabilities. The analysis should align with FDA guidance on cybersecurity. * **Sterilization and Shelf Life:** Testing must be performed on the final, assembled, and packaged device. ### Risk Analysis Focus The risk analysis (per ISO 14971) must include a specific focus on hazards arising from the **integration** of technologies. * **Hazard Identification:** Brainstorm potential hazards that could only exist because the components are combined. Examples include thermal interference (heat from one component affecting another), material degradation due to chemical incompatibility, or software conflicts. * **Risk Mitigation:** Document the specific design features and verification/validation tests used to mitigate these integration-specific risks. --- ## Strategic Considerations and the Role of Q-Submission Using a multiple predicate strategy increases regulatory complexity and the risk of receiving an Additional Information (AI) request or a Not Substantially Equivalent (NSE) decision. Engaging the FDA through the Q-Submission program is the most effective tool for mitigating this risk. A Pre-Submission (Q-Sub) meeting or written feedback request allows a sponsor to gain early FDA feedback on their proposed strategy. Key questions to include in a Q-Sub for this scenario are: 1. **Predicate Strategy:** "We have selected [Predicate X] as the primary predicate and [Reference Device Y] to support our device's [specific feature]. Does the Agency agree with this predicate strategy?" 2. **Comparison Structure:** "We plan to structure our substantial equivalence comparison as described in this package. Is this approach clear, and does the Agency have any recommendations for improving the clarity of our comparison?" 3. **Testing Plan:** "We have identified potential integration risks between [Feature 1] and [Feature 2]. Does the Agency agree that our proposed system-level testing plan is adequate to address these risks?" 4. **Intended Use:** "Based on our proposed intended use statement, does the Agency believe the device raises different questions of safety or effectiveness when compared to the predicate devices?" Presenting a well-reasoned argument and a detailed testing plan in a Q-Sub can build confidence with the FDA and streamline the final 510(k) review. --- ### 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 a complex 510(k) submission with multiple predicates requires meticulous organization. Regulatory management platforms can help teams structure their submission, manage complex device comparison tables, and link specific performance testing evidence directly to claims made against both primary and reference predicates. This ensures that the final submission package presents a clear, logical, and well-supported argument for substantial equivalence. *** *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.*