The article describes in detail another type of submission – a special supplement. In particular, the article provides an overview of the applicable regulatory framework and also explains the examples illustrating the situations when a special supplement will be appropriate, and also highlights the key aspects to be considered when determining the applicability of the said pathway.
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). In particular, the document describes in detail the PMA supplement decision-making process – the way the party responsible for a medical device should determine the particular type of supplement to be used, and the key factors to be considered in this respect.
It is important to mention that the present FDA guidance is non-binding in its legal nature, and is not intended to introduce new rules or impose new obligations. Instead, the document provides additional clarifications regarding the existing regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved to ensure compliance thereto. At the same time, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing legislation and has been agreed with the authority in advance.
The guidance describes in detail the main types of supplements including, inter alia, the following ones:
- Traditional PMA;
- Panel-Track Supplement;
- 180-Day Supplement;
- Real-Time Supplement; and
- Special PMA Supplement.
Special PMA Supplement: Key Points
According to the guidance, the use of a special PMA supplement is regulated under Section 21 CFR 814.39(d)(1) and (d)(2). As further explained by the FDA, the Special PMA Supplement is a narrow exception to the general rule that prior FDA approval of changes to a PMA, including the labeling for a device, is a condition of lawful distribution and, therefore, may only be utilized when (1) the applicant has newly acquired safety-related information; (2) the information in question was not previously submitted to the FDA; and (3) the information involves labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction for which there is reasonable evidence of a causal association.
Under the general rule, the authority reviews carefully any changes to the labeling suggested by the manufacturer to ensure they are substantiated by sufficient evidence. At the same time, when using a Special PMA Supplement, the manufacturer will be able to make such changes while making references to the information already known to the authority. Such an approach will allow to simplify and streamline the process and also reduce the regulatory burden. The authority also mentions that it is not allowed for the manufacturer to add safety warnings intended to avoid potential liability in case of any issues related to the device. The present pathway should be used only in case the manufacturer obtains new information which is important to be reflected in the labeling to ensure the device will be used safely and efficiently.
Considering the Applicability
As further explained by the FDA, the changes could be implemented even before the respective approval will be granted by the authority in case the following conditions are met:
- The PMA supplement and its mailing cover are marked “Special PMA Supplement – Changes Being Effected”;
- The PMA supplement provides a full explanation of the basis for the changes;
- The applicant has received acknowledgment from the FDA of receipt of the supplement; and
- The PMA supplement specifically identifies the date that such changes are being affected.
At the same time, the authority additionally emphasizes that even if the changes could be implemented before the approval, such changes will be deemed temporary within the period the authority will need to review the request. Furthermore, it is also stated that the design changes are not admissible within the scope of a Special PMA Supplement. The authority provides an example of a situation when the manufacturer intends to make significant changes to the implantable medical device that would affect its safety – such changes will not be appropriate for a Special PMA Supplement.
As further explained by the FDA, the framework described herein is mostly intended to be used in case of changes to the labeling, even though some other changes (e.g., the ones related to the quality control or manufacturing process) could be appropriate for it as well. In particular, it is stated that the manufacturing changes that may be reviewed as a Special PMA Supplement are generally those that add a step to the quality control or manufacturing processes to enhance safety but not to impact effectiveness. At the same time, if the changes to be implemented are expected to impact the actual effectiveness and performance of the device as well, other types of supplements should be used.
To assist medical device manufacturers in understanding and following the approach described herein, the authority also provides several examples of the situations in which a Special PMA Supplement could be used. The examples include, inter alia, the following ones:
- New warning added (no changes to the effectiveness).
- Manufacturing process changes, including the ones intended to improve safety, provided they are not affecting the performance of the device.
- General improvements for the instructions for use accompanying the device.
- Adding new inspection steps in the manufacturing process.
In summary, the present FDA guidance provides an overview of the regulatory requirements related to a Special PMA Supplement and outlines the scope of situations in which this type of supplement will be appropriate. The document highlights the main factors to be considered when deciding the applicability of the said framework and explains the way the changes in question should be analyzed.
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