How do I justify substantial equivalence with multiple predicate devices?

## Justifying Substantial Equivalence: A Guide to Using Multiple Predicate Devices in a 510(k) For medical device manufacturers pursuing clearance through the FDA 510(k) program, selecting an appropriate predicate device is a foundational step. However, for innovative devices that combine features from multiple existing technologies, a single predicate may not exist. In these situations, manufacturers may use a "split predicate" approach, referencing two or more legally marketed devices to demonstrate substantial equivalence. While this strategy is permissible under the 510(k) framework, it places a significant burden on the sponsor to provide a clear and compelling justification. A successful split predicate 510(k) submission hinges on a robust scientific rationale that demonstrates the new device is as safe and effective as its predecessors. The core challenge is to prove that the *combination* of features from different predicates does not introduce new questions of safety or effectiveness. This requires a meticulous comparison and targeted performance data that specifically addresses the risks of integrating these previously separate elements. ### Key Points * **Robust Justification is Essential:** The sponsor must provide a comprehensive scientific rationale explaining why the combination of features from multiple predicates is safe and effective and does not create a new intended use. * **Detailed Feature Mapping:** A successful submission requires a detailed side-by-side comparison table that clearly maps every feature, technology, and characteristic of the new device to a corresponding legally marketed predicate. * **Address Integration Risks:** The primary focus of the FDA's review will be on the risks introduced by integrating disparate features. The justification must proactively identify and mitigate these potential risks. * **Targeted Performance Testing:** Performance data must go beyond what was required for the individual predicates. Testing should specifically validate the safety and performance of the combined, final device. * **Early FDA Engagement is Recommended:** Due to the increased complexity and risk of a Not Substantially Equivalent (NSE) finding, engaging with the FDA through the Q-Submission program to discuss the predicate strategy is a highly recommended best practice. ### Understanding the "Split Predicate" Strategy A split predicate strategy is used when a new device incorporates features from more than one legally marketed device, and no single device serves as a suitable primary predicate. The goal is to demonstrate that the new device's intended use and technological characteristics are substantially equivalent to the predicates, even if the features are drawn from different sources. For example, consider a new Software as a Medical Device (SaMD) that: 1. Uses a novel image processing algorithm cleared in **Predicate A**. 2. Displays the output on a user interface and platform established by **Predicate B**. In this case, the sponsor would argue that the core diagnostic technology is equivalent to Predicate A, while the user-facing technology is equivalent to Predicate B. The key regulatory question is whether combining this specific algorithm with this specific user interface raises new issues that neither predicate faced individually. ### Building a Robust Justification A split predicate argument must be structured, logical, and supported by strong evidence. Simply stating that features come from cleared devices is insufficient. #### Detailed Feature-by-Feature Comparison The foundation of the argument is a meticulous side-by-side comparison table. This table should break down the new device and each predicate into granular detail, covering: * **Intended Use and Indications for Use:** The new device's intended use cannot be a novel combination that creates a fundamentally new clinical application. * **Technological Characteristics:** This includes principles of operation, materials, software algorithms, energy sources, and other key specifications. * **Performance Specifications:** Bench testing, biocompatibility, software validation, and other performance data. For every feature of the new device, the table must point to the specific predicate that shares that feature. Any differences must be clearly identified and justified as not raising new questions of safety or effectiveness. #### The Scientific Rationale and Risk Mitigation Beyond the comparison table, the submission must include a strong scientific narrative. This rationale should explain *why* the combination of features is safe. It must proactively address potential integration risks, such as: * **Negative Interactions:** Could the materials from one predicate negatively interact with the technology of another? * **New Failure Modes:** Does the integration create failure modes that were not possible in the individual predicates? * **Human Factors Issues:** In the SaMD example, could the user interface from Predicate B cause a user to misinterpret the output from the algorithm of Predicate A? This rationale should be supported by a thorough risk analysis conducted on the final, integrated device. ### Scenario: An Orthopedic Implant with a New Combination of Features #### Scenario Description A manufacturer develops a new spinal fusion cage. The cage uses a well-established geometry and base material (**Predicate A**), but incorporates a novel surface coating technology that was previously cleared on a different type of orthopedic implant, like a hip screw (**Predicate B**). * **What FDA Will Scrutinize:** * The biocompatibility of the coating when applied to the new base material of the spinal cage. * The mechanical integrity of the cage. Does the coating process weaken the implant? Is the coating susceptible to delamination or wear under the unique biomechanical stresses of the spine? * Whether the combination of the cage's geometry and the coating's properties could lead to unforeseen adverse tissue reactions. * **Critical Performance Data to Provide:** * Comprehensive biocompatibility testing on the final, coated spinal cage. * Mechanical testing (e.g., static and dynamic compression, expulsion testing) to demonstrate that the coated device performs as well as Predicate A. * Wear and particle analysis to ensure the coating remains adhered to the device under simulated physiological conditions. ### Strategic Considerations and the Role of Q-Submission A split predicate strategy inherently carries more risk than a 510(k) submission with a single, strong predicate. If the FDA determines that the combination of features raises new questions of safety or effectiveness, it may issue an NSE decision, which would require the sponsor to pursue a more burdensome De Novo or PMA pathway. To mitigate this risk, early engagement with the FDA through the Q-Submission program is highly valuable. A Pre-Submission (Pre-Sub) meeting allows a sponsor to present their proposed predicate strategy, comparison table, and testing plan. This provides an opportunity to get direct FDA feedback on the appropriateness of the chosen predicates and the adequacy of the justification plan *before* committing to expensive testing and submission preparation. ### 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 split predicate 510(k) requires exceptional organization. Tools like Cruxi can help teams structure their regulatory strategy by creating detailed comparison tables, mapping device features to predicate evidence, and managing the extensive documentation required to build a compelling scientific rationale. This ensures that all elements of the justification are logically linked and supported by the necessary performance data. *** *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.*