The article provides an overview of the regulatory requirements related to the modifications to devices subject to premarket approval.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to modifications to devices subject to Premarket Approval (PMA) – the PMA supplement decision-making process. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved in operations with medical devices intended to be marketed and used in the US. At the same time, due to the nature of the guidance, provisions thereof are non-binding, and are not intended to introduce new rules or impose new obligations the parties involved should comply with. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the respective regulations and has been agreed with the authority in advance. The authority also reserves the right to make changes to the guidance and recommendations provided therein, should it be reasonably necessary to reflect the respective changes to the underlying legislation.
As it is stated by the FDA, the guidance document has been developed to provide the underlying principles and examples to establish a clear and consistent way to approach the decision-making process [the manufacturer should] follow to determine the type of regulatory submission if any, that may be required when [the manufacturer] modifies [its] lawfully marketed PMA device.
The scope of the guidance covers the products classified as Class III medical devices that are subject to premarket approval application (PMA) requirements. In particular, the document outlines the specific criteria to be applied when determining the type of PMA submission required in case of changes to the design or labeling of the device in question; the manufacturing process and facilities, or the packaging of the product. For this purpose, the authority provides several examples of such modifications and explains the regulatory approach to be applied in each of the cases, including the testing required and the application to be submitted. At the same time, the authority additionally emphasizes that the present guidance does not address how to test a specific device to determine the effects of modifications. The scope of the guidance also covers the cases when modifications to the medical device already placed on the market are made in the course of a recall or field corrective action intended to ensure compliance with the respective safety and performance requirements. It is also important to mention that the present guidance does not substitute any of the existing guidance documents dedicated to the PMA framework.
The authority also states that the regulatory approach described in the guidance is the least burdensome. As explained by the FDA, the authority evaluates carefully all the aspects related to the products in question and risks associated thereto to ensure medical device manufacturers and other parties involved are not subject to unneeded regulatory burden, while ensuring that any products allowed for marketing and use in the US comply with the applicable safety, quality and effectiveness requirements set forth by the existing legislation.
According to the guidance, the general criteria to be applied when determining the need for a PMA supplement or a 30-day notice are outlined in regulation 21 CFR Part 814 (PMA regulation). In particular, the details are provided in subparts B “Premarket Approval Applications” and E “Post Approval Requirements”, including the aspects related to the continuing evaluation, reporting, and other matters related to the safety and effectiveness of the products placed on the market.
This guidance document is intended to provide additional clarifications regarding the interpretation of the PMA regulation in terms of submissions related to changes to the device depending on the impact such changes are expected to cause on the safety and effectiveness of the device in question. The authority also mentions that there was a request from the industry representatives to provide a flowchart describing the applicable regulatory procedures step-by-step to ensure that the applicable regulatory requirements are interpreted and followed correctly. However, the authority states that due to the complexity of the matter, and variability of the products covered by the scope of regulation, resulting in variability of the approaches to be applied, such a flowchart cannot be developed. Apart from this, the industry representatives also requested FDA to provide definitions of the most important terms and concepts, such as “substantial clinical data”, “significant change”, and “limited confirmatory clinical data”. The authority provides additional clarifications regarding the way the said terms should be applied and interpreted, however, it also states that in some cases it is difficult to provide precise definitions, so the examples illustrating the correct interpretation are provided instead. The FDA also mentions that 30-day supplements are not covered by the scope of the present guidance, even though it was requested by the industry representatives.
General Requirements: Changes
First of all, the guidance outlines the scope of changes for which a PMA supplement will be required in case such changes are expected to impact the safety or effectiveness of the medical device placed on the market. According to the guidance, such changes include, inter alia, the following ones:
- New indications for use of the device;
- Labeling changes;
- The use of a different facility or establishment to manufacture, process, or package the device;
- Changes in sterilization procedures;
- Changes in packaging;
- Changes in the performance or design specifications, circuits, components, ingredients, the principle of operation, or physical layout of the device; and
- Extension of the expiration date of the device based on data obtained under a new or revised shelf life testing protocol that has not been approved by the FDA (it is stated that in case the authority has already approved the respective protocol the information about the changes should be included in a periodic report).
In summary, the present FDA guidance provides an overview of the regulatory requirements and describes the approach to be applied concerning changes to Class III medical devices placed on the market. The document provides clarifications regarding the way the PMA changes supplement framework should be applied and highlights the most important aspects associated thereto.
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