The concept of ‘substantial equivalence’ is the foundation of the US FDA pre-market authorization (510(k)) marketing pathway and demonstration of substantial equivalence is the core consideration for US FDA reviewers during their review of 510(k) submissions. It is also critical in determining whether a device requires a De Novo (513(f)(2) submission. In this article, we cover the concept of ‘substantial equivalence’ and related terminology/considerations.
The Definition of ‘Substantial Equivalence’ and ‘Predicate Devices’
Under section 513(f) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a new (post-amendments[1]) device is automatically in Class III (subject to pre-market approval (PMA) or reclassification before marketing), unless:
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- It is a type of device that was in commercial distribution before May 28, 1976 (i.e. pre-amendment device), and is substantially equivalent to another such device; OR
- It is within a type of device introduced after May 28, 1976, that has been reclassified into Class I or II and is substantially equivalent to another device within such classification.
Under 21 CFR Part 807, devices that fall under either of the above categories are subject to pre-market notification (510(k)) requirements.
The standard for US FDA determination of substantial is established in section 513(i) of the FD&C Act as:
“(i)(1)(A) For purposes of determinations of substantial equivalence under subsection (f) and section 520(l), the term “substantially equivalent” or “substantial equivalence” means, with respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that the Secretary by order has found that the device (i) has the same technological characteristics as the predicate device, or (ii)(I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including appropriate clinical or scientific data if deemed necessary by the Secretary or a person accredited under section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and (II) does not raise different questions of safety and effectiveness than the predicate device. B) For purposes of subparagraph (A), the term “different technological characteristics” means, concerning a device being compared to a predicate device, that there is a significant change in the materials, design, energy source, or other features of the device from those of the predicate device.”
What is a predicate device regarding substantially equivalence under the FDA?
The term ‘predicate device’ used above refers to a legally marketed device with which the new device shall be substantially equivalent (NOTE: ‘predicate devices’ are also referred to simply as ‘predicates’). Under 21 CFR Part 807, a legally marketed device is one that:
[1] A ‘post-amendments device’ is a device introduced after the Medical Device Amendments to the FD&C Act were enacted on May 28, 1976, while a ‘pre-amendments device is a device introduced prior to this date.
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- Is a pre-amendments device and for which a PMA is not required;
- Has been reclassified from Class III to Class II or I (e.g. Devices marketed in the US under a De Novo determination);
- Has been found substantially equivalent through the 510(k) pathway.
As device safety and effectiveness are considered during the US FDA 510(k) review, the manufacturer must demonstrate that its device and the predicate have the same intended use, although changes in indications for use are possible (so long as they do not (or may not) affect the safety and/or effectiveness of the new device as compared to the predicate and the differences can be adequately assessed). You may recall, from our article on determining US FDA device classification, that the “intended use” of a device is its general purpose or function and includes the indications for use, whereas the “indications for use” describe the disease or condition a device will diagnose treat, prevent, cure or mitigate, including a description of the patient population for which the device is intended. A good example of the difference between “intended use” and “indications for use” provided by the US FDA on its website is that for a scalpel. In this case, the intended use of a scalpel is to cut tissue, whereas an indication for use could be for making incisions in the cornea. In determining whether this scalpel used for making incisions in the cornea could be a suitable predicate for a scalpel indicated for making incisions in another anatomical location, an assessment of the impact this difference in indication has on the safety and effectiveness of the new device would be performed by the US FDA during their review.
While it is mandatory to identify a predicate in all 510(k) submissions, manufacturers can identify multiple predicates (although the US FDA encourages the use of a single predicate to simplify the process, where possible). However, where multiple predicates are identified in a 510(k), manufacturers should clearly identify the ‘primary predicate’ which is the predicate with indications for use and technological characteristics most similar to the new device. The flowchart below demonstrates the decision-making process for demonstrating substantial equivalence:
Where devices have the same intended use and technological characteristics, a demonstration of FDA substantial equivalence is straightforward. One of the most common challenges confronted by manufacturers is demonstrating substantial equivalence for devices with the same intended use but different technological characteristics.
Technical Differences Regarding Predicate and New Devices
In determining the impact of technological differences between the predicate and the new device, the US FDA will assess the following:
1. Do the Different Technological Characteristics of the Devices raise Different Questions of Safety and Effectiveness?
To allow the US FDA reviewer to determine whether any different technological differences between a new device and predicate raise different questions of safety and effectiveness, the manufacturer should ensure that all such characteristics (e.g. materials, design, energy sources, mechanisms of action, etc.) are clearly identified for both the new device and predicate in their 510(k) – the easiest way to do so is typically in a comparative table.
With this information, and information available in its own files, the US FDA identifies the differences and determines, where they exist, whether they raise different questions of safety and effectiveness. In other words, the reviewer will determine whether there are any questions raised by the different (new or changed) technological characteristics that was not applicable to the predicate, that pose a significant safety or effectiveness concern for the new device.
For example, both a new device and predicate are surgical shears intended to seal and cut and/or dissect and coagulate soft tissue, however the new device performs it’s intended use through the application of ultrasonic energy to soft tissue while the predicate performs it’s intended use through the application of mechanical energy. In this scenario, the difference in energy sources do raise different questions of safety and effectiveness, such as the generation of surgical plumes by the new device, which was not applicable to the predicate. In this scenario, the FDA reviewer would determine that these devices are not substantially equivalent.
2. Are the Proposed Scientific Methods for Evaluating New/Different Characteristics’ Effects on Safety and Effectiveness Acceptable?
Where the US FDA reviewer has determined that there are differences in the technological characteristics between the new and predicate device but they do not raise different questions of safety and effectiveness, the reviewer will focus on the performance data provided with the 510(k), including the scientific methods applied by the manufacturer in assessing these new/different characteristics and their effects on safety and effectiveness. It is at this stage that the use of ‘reference devices’ may be a consideration in the 510(k). A ‘reference device’ is not a ‘predicate device’. A ‘reference device’ is a legally marketed device that is intended to provide scientific and/or technical information (e.g. test methodology) to help address the safety and effectiveness of a new technological characteristics. Any 510(k) submission that includes the use of a ‘reference device’ should include a scientific rationale that justifies its use, as the applicability of reference devices is subject to US FDA reviewer scrutiny for appropriateness.
Regarding the scientific methods applied, the application of relevant US FDA recognized consensus standards and guidance documents is one way to ensure their acceptability. While compliance with such standards and guidance is not mandatory, unless otherwise stated, manufacturers should expect more challenging reviews if they have not been applied.
3. Do (non-clinical and/or clinical) Performance Data Demonstrate Substantial Equivalence?
The US FDA reviews performance data in a stepwise manner to ensure that requests for information (RFI) during the iterative review are aligned with the least burdensome approach adopted by the agency. This means that following review of the descriptive information and non-clinical performance data presented in the 510(k), the reviewer will only request clinical performance data where if the non-clinical performance data is insufficient to support a determination of FDA substantial equivalence. Even with non-clinical performance data, non-clinical animal studies and/or biocompatibility testing are typically requested only when other types of non-clinical performance testing are deemed insufficient. This includes performance data on reference devices. Even then, current US FDA guidance also covers scenarios where biocompatibility testing is unnecessary or where additional testing is expected compared to other international markets.
This article provides an overview of ‘substantial equivalence’ under the US FDA regulatory framework, however if you have any questions on entering the US device market, including 510(k) compilation/submission, or require a US Agent, or require relevant training / consulting services, get in touch.