FDA New Draft Guidance: Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions

Introduction

This draft guidance from the FDA provides recommendations for when and how clinical data may be necessary and appropriate to include in 510(k) premarket notification submissions for medical devices. It outlines four scenarios where clinical data could be needed to determine if a new device is substantially equivalent to a predicate device:

1. If the proposed and predicate devices have differences in their intended uses or indications

2. If there are differences in their technological characteristics

3. If substantial equivalence cannot be determined through non-clinical testing alone

4. If new risks have been identified for the predicate device

The guidance aims to help industry understand the appropriate use of clinical data in the 510(k) process and when such data may be necessary for FDA's substantial equivalence determination. It is part of FDA's efforts to modernize and strengthen the 510(k) program as outlined in the agency's Medical Device Safety Action Plan.

Guidance

This guidance provides additional context and clarity on when clinical data may be necessary to demonstrate substantial equivalence as part of the 510(k) premarket notification process. It further describes scenarios outlined in previous guidance where clinical data could be needed, provides another scenario, and offers additional examples. The intent is to enhance predictability, consistency and transparency around the use of clinical data in 510(k) submissions. While guidance documents themselves do not establish legally enforceable responsibilities, following them helps protect and promote public health. The Safety Action Plan and additional modernization steps announced in 2018 aimed to improve device safety while creating more efficient pathways. Public comments on these initiatives noted a need for more clarity on clinical data use in 510(k) reviews.

A 510(k) submission is required for new devices intended for human use that are not exempt and for which a premarket approval is not needed, to determine if the device is substantially equivalent to a predicate device. This guidance clarifies when clinical data may be necessary to make that substantial equivalence determination.

Substantial Equivalence

This guidance discusses the FDA's criteria for determining substantial equivalence (SE) between new medical devices and previously approved predicate devices through the 510(k) premarket notification process. For a new device to be found SE to a predicate, the FDA must determine that they have the same intended use and the same technological characteristics, or if different characteristics, that the differences do not raise new questions of safety and effectiveness and the new device is as safe and effective as the predicate. The FDA evaluates the benefit-risk profile of the new device in comparison to the predicate. In many cases, non-clinical data like performance and safety testing is sufficient to demonstrate SE without clinical data. However, for some devices clinical data may be necessary if non-clinical data is insufficient to determine the new device is as safe and effective as the predicate.

Recommendations

This guidance provides recommendations for manufacturers submitting 510(k) premarket notifications to the FDA. It encourages manufacturers to reduce animal testing when feasible by consulting with the FDA about using alternative non-animal testing methods. If alternative methods are proposed but not deemed acceptable, the FDA may request clinical performance data to support a substantial equivalence determination. Such clinical data could include comparisons between new and predicate devices, data on changed intended uses or benefit-risk assessments. Clinical data submitted should constitute valid scientific evidence. It may include results from clinical investigations, literature reports on comparable devices, clinical experience reports, registries, adverse events and medical records. Real-world data relevance and reliability should be considered. When data on comparable devices is provided, adequate justification of applicability to the new device is needed. In some cases, non-clinical data may also be needed to show device comparability. Data from human factors testing is not clinical data. The guidance scope covers recommendations for 510(k) submissions.

Summary

The guidance provides recommendations on when clinical data may be needed to demonstrate substantial equivalence (SE) for a device reviewed under the 510(k) premarket notification program. It aims to improve the predictability, consistency, and transparency of the 510(k) review process. The guidance describes scenarios where clinical data could help determine SE, such as when a new device and predicate have the same intended use but different technological characteristics that raise questions about safety and effectiveness. Clinical data is typically reviewed in such cases to determine if the new device is as safe and effective as the predicate. The guidance notes clinical data may also be considered at other stages, like determining whether new or modified intended uses fall within the same use as the predicate. It does not describe situations requiring postmarket clinical data collection or change existing regulatory standards or requirements. The principles apply to devices reviewed by the Center for Devices and Radiological Health and Center for Biologics Evaluation and Research. It is not meant to replace device-specific guidance and does not address review issues unique to combination products.

Discusses Four Scenarios Where Clinical Data May Be Necessary to Demonstrate Substantial Equivalence (SE)

- There are differences between the indications for use of the new device and predicate device that may require clinical data to determine SE.

- There are differences in technological characteristics between the devices that may require clinical data to determine SE.

- SE cannot be determined through non-clinical testing alone.

- A newly identified or increased risk for the predicate device suggests clinical data may be needed for the new device to determine SE.

Scenario 1: Differences in Indications for Use

- Factors such as differences in patient population, disease, anatomical site, and whether the new device expands on an existing clearance or has an unknown risk profile may require clinical data to support differences in indications for use between the new and predicate devices.

- Examples of when clinical data may or may not be needed to support differences in indications for use between the new and predicate devices.

Discusses When Clinical Data May Be Needed in 510(k) Submissions to Demonstrate Substantial Equivalence (SE)

- When the new device is intended for use in a higher risk population than the predicate device.

- When the new device is intended for use in a different anatomic location that presents increased risk.

- When there are differences in technological characteristics between the new and predicate devices that raise different questions about safety and effectiveness.

- When the new intended use does not represent a new risk compared to the predicate device, non-clinical data may suffice to demonstrate SE.

- Clinical data allows establishing that a new device with different characteristics performs equivalent to the predicate device despite those differences.

Discusses Considerations for When Clinical Data May Be Necessary

- When there are significant changes in materials, device design, energy source, or other device features.

- Examples include when a device is made of resorbable material instead of non-resorbable, when a new monoclonal antibody clone is used in an in vitro diagnostic device, or when new sizes of an implanted device would expand the range of cleared device sizes.

- When non-clinical testing is not adequate to establish SE, such as when there is no adequate model for testing, models have limitations, or models cannot predict clinical outcomes. Examples include a device for treating schizophrenia and a medical image system adding new organ-specific processing features.

Discusses Scenarios Where Clinical Data May Be Necessary

- When bench or animal testing is not predictive of human performance due to differences between animal and human physiology (e.g. for hemostatic devices).

- When analytical testing alone cannot evaluate clinical performance or risks associated with incorrect results (e.g. for blood screening devices).

- For point-of-care in vitro diagnostic devices, due to varied clinical environments and populations affecting real-world performance.

- For aesthetic devices with no appropriate animal models, clinical data may be needed to evaluate effectiveness and translate measures to humans.

- Even without technological differences, clinical data may be required if new safety risks have been identified for the predicate device from post-market data sources, to determine SE in light of new risk information. The FDA communicates new risk information and may request additional clinical data during review.

Discusses FDA's Approach to Requesting Additional Data

- Example 4-A describes a device with known malfunctions but where FDA determined detailed non-clinical testing could adequately demonstrate safety for new 510(k) submissions, without needing additional clinical data.

- Example 4-B describes a device that was cleared without clinical data but later recalls and postmarket surveillance suggested safety concerns related to component failure, leading FDA to request clinical data in 510(k)s and issue a postmarket surveillance study order.

- Example 4-C describes a device issue that could cause significant patient injury, where the manufacturer submitted a new 510(k) with non-clinical and clinical data to address the issue because changes could affect safety or effectiveness. FDA issued guidance outlining recommendations for performance testing.