The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a final guidance document dedicated to the submission of 510(k) notifications for changes to medical devices that have already been placed on the market. The draft version of the guidance was issued by the authority earlier in August 2016. Due to its legal nature, the document does not introduce any rules or requirements itself but provides additional clarifications and recommendations to be considered by all the parties involved.
The Agency also states that an alternative approach could be applied, provided such an approach complies with the applicable regulatory requirements and has been approved by the authority in advance. The FDA also reserves the right to amend the guidelines and change the recommendations provided therein, should it be reasonably necessary to reflect the changes in the applicable legislation.
Regulatory Background
The document describes in detail the current regulatory requirements in order to assist medical device manufacturers in determining the particular situations when changes made to a medical device already placed on the market require submission of a new 510(k) notification. The authority intends to describe the least burdensome approach and provides additional clarifications regarding the way existing rules should be applied.
The document also contains references to the FDA-recognized standards, which could be used by the medical device manufacturers to demonstrate conformity with the applicable regulatory requirements.
According to 21 CFR 807.81(a)(3), which is the applicable regulation in the case of notification requirements, such notification should be submitted if:
(3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification:
(i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.
(ii) A major change or modification in the intended use of the device.
The authority acknowledges that the terms “significant” and “major” could have different interpretations, resulting in compliance issues when determining the necessity of submitting a 510(k) notification for changes. The present guidance is intended to provide additional clarifications regarding the interpretation of the above-mentioned terms in a proper way.
Quality System Regulation
The FDA additionally emphasizes the importance of the Quality System (QS) regulation. For instance, in certain cases, the requirement to submit a new 510(k) notification could be waived, provided that the manufacturer will refer to the current QS requirements when demonstrating compliance for a modified device. According to the QS regulation, the medical device manufacturer shall:
- Review and approve changes to devices design,
- Document changes and approvals in the device master record,
- Validate any process whose results cannot be fully verified by subsequent inspection and testing, and
- Review, evaluate, revalidate the process when it is reasonably necessary due to the changes made thereto.
The QS regulation prescribes the way the manufacturer shall demonstrate that the modified device still complies with any and all applicable regulatory requirements. Additionally, the medical device manufacturer shall duly document all the changes made and keep these records to be able to provide them to the authority once requested, even if the changes do not require submission of a new 510(k) notification. However, according to the applicable regulation, the scope of information the authority may request is limited to the information reasonably necessary to assess the changes and evaluate the impact they have on the safety and effectiveness of a medical device. From the regulatory standpoint, such an approach reduces to the minimum extent possible the regulatory burden on the manufacturers and simplifies the way they can demonstrate equivalence to medical devices already placed on the market, which is the easiest way to confirm that the new device complies with any and all regulatory requirements as well.
Scope of Applicability
The scope of the present guidance covers modifications made to the medical devices already placed on the market under the 510(k) framework, including novel devices authorized under the De Novo classification process. The document is intended to provide additional clarifications to be considered when determining whether the changes made to a cleared device exceed the regulatory threshold behind which a new 510(k) submission is required. The authority emphasizes that the medical device subject to change should not be placed on the market before being assessed and approved by the authority unless such changes do not require any approval. At the same time, the scope of the present guidance does not cover software products – the appropriate regulatory matters are addressed in separate guidance. The recommendations provided in the document also should not be applied in case of changes made to combination products, while the general approach described herein could still be used with regard to device parts of combination products.
Core Principles
The approach to be applied when determining whether the changes made to a medical device require a separate 510(k) submission is based on several key principles to be considered by the medical device manufacturer, namely:
1. Changes made with intent to significantly affect the safety or effectiveness of a device. If the changes the manufacturer intends to make to the device already placed on the market could cause a significant impact on its safety and performance, such changes will require a new 510(k) submission. Thus, the manufacturer shall evaluate and assess the impact the planned changes will potentially have.
1. Initial risk-based assessment. At the very first step, the manufacturer shall assess rigorously the expected impact of modifications to be made in terms of the risks associated with the use of a medical device in question.
2. Unintended consequences of changes. Apart from intended changes in safety and performance, the manufacturer shall also assess the consequences the suggested changes could potentially result in. In this regard, the manufacturer shall analyze reasonably expected risks and evaluate them in terms of the benefit-risk perspective.
3. Use of risk management. As mentioned, the manufacturer shall pay exceptional attention to risks associated with the medical device in question and also to the way such risks are changing due to the modification made.
4. The role of testing (i.e., verification and validation activities) in evaluating whether a change could significantly affect safety and effectiveness. Should the manufacturer decided that for the particular modifications to be made, a new 510(k) submission is not required, the appropriate validation should be performed in order to confirm such a decision.
5. Evaluating simultaneous changes to determine whether the submission of a new 510(k) is required.
6. Appropriate comparative device and the cumulative effect of changes.
7. Documentation requirement.
8. 510(k) submissions for modified devices.
9. Substantial equivalence determination.
In summary, the present FDA guidance describes the most important factors to be considered by medical device manufacturers when determining whether changes made to a device already placed on the market require a new 510(k) submission. The Agency describes in detail the main principles to be applied and provides additional clarifications with regard to the current regulatory requirements.
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