What products would the proposed rules cover?

The proposed rules, Rule 1 and Rule 2, would implement classification of currently unclassified, pre-amendments wound dressings and liquid wound washes containing antimicrobials and/or other chemicals. Such products are currently regulated through the 510(k) pathway. The proposed classification is informed largely by feedback taken from previous FDA panel meetings held in 2005 and 2016, which we summarized online here. The rules would apply to the following products that contain antimicrobials or certain other chemicals:

1. solid wound dressings, the intended use for which is to cover and protect a wound, to absorb exudate, and to maintain appropriate moisture balance within the wound;

2. wound dressings formulated as a gel, cream, or ointment, the intended use for which is to maintain appropriate moisture balance within the wound; and,

3. liquid wound washes, the intended use for which is to mechanically irrigate and physically remove debris from external wounds.

To be within the scope of the proposed medical device classification rules, antimicrobials could only be included within these wound dressings and liquid wound washes for two functions or roles to support the use of the dressing or wash: (1) as a preservative or (2) as a protectant of the product such as to reduce microbial growth within the solid wound dressing while in use, or to provide an antimicrobial barrier to microbial penetration through the solid wound dressing. Antimicrobials that are not used solely to support the use of the wound dressings formulated as a gel, cream, or ointment or liquid wound washes by preventing or reducing contamination or deterioration thereof while in its packaging, or those in which the use is not scientifically needed, are not considered preservatives for the purposes of these proposed rules. While not stated in the proposed rules explicitly, such additional functions for the antimicrobial substances would presumptively lead to combination product assessments for designation purposes based on primary intended effects and modes of operation.

Apart from antimicrobials, the proposed rules clarify that wound dressings and liquid wound washes also may contain “other chemicals” including wound protectants, honey, synthetic peptides, and botanical extracts. Specifically, Rule 1 only addresses other chemicals used to contribute to the uses of wound dressings and liquid wound washes by physical means. Importantly, ingredients that achieve their primary intended purposes through chemical action would not fall under the “other chemicals” category. The proposed rules also exclude wound dressings and liquid wound washes containing animal-derived materials without the presence of antimicrobials or other chemicals.

Examples of antimicrobials and “other chemicals” contemplated by Rule 1 are found in tables 2 and 3 of the rule, “Classification of Certain Solid Wound Dressings; Wound Dressings Formulated as a Gel, Creams, or Ointment; and Liquid Wound Washes.” Tables 4-6 of Rule 1 depict how each agency-identified “risk to health” would be mitigated by the proposed special controls.

Notably, the proposals cover both medical devices that have not been offered for sale prior to the effective date of the final rule, as well as devices proposed to be classified into class II that have prior 510(k) clearance as unclassified devices.

How would FDA classify the products under the proposed rules?

FDA currently regulates wound dressings and liquid wound washes containing antimicrobials (hereinafter collectively, “wound products”) as unclassified medical devices requiring premarket notification (510(k)) to be marketed in the U.S. FDA is now proposing to classify these wound products as class III if they contain substances (drugs or other chemicals) that have a high level of antimicrobial resistance (AMR) concern and as class II (subject to defined special controls) for wound products carrying medium or low level of AMR concern.

Under the proposed rules, wound dressings and washes that contain “medically important” antimicrobials acting as protectants or preservatives would be classified as class III products due to their high level of AMR concern. Wound dressings and washes with antimicrobials presenting medium or low level of AMR concern would be categorized as class II (special controls). Rule 1 defines “medically important” antimicrobials as those that are important for therapeutic use in humans, referring to an external list of classes of antimicrobials published by the World Health Organization (WHO).[1] Of note, the rule further specifies that “an antimicrobial is considered medically important, if and only if, it falls within any of these classes regardless of the level of importance specified by the WHO (i.e., critically important, highly important, or important).” Considering that WHO updates this list every couple of years, it remains to be seen how changes to WHO’s classification of antimicrobials may affect the FDA regulation of products containing affected antimicrobials, or how WHO’s evolving understanding of antimicrobial resistance may influence FDA’s enforcement priorities. Currently, this list of medically important antimicrobials that have been incorporated in FDA-cleared wound care products impacted by these proposed rules include: Silver sulfadiazine, Polymyxin B, and Bacitracin.

For devices with medium/low AMR substances, the proposed rules emphasize that general controls alone are not sufficient to demonstrate a reasonable assurance of the device’s safety and effectiveness, and therefore special controls must be met, as proposed under 21 C.F.R. §§ 878.4016(b)(2). In addition to standard testing requirements for the product such as specification verification, the special controls include antimicrobial characterization and performance testing supporting performance under intended use and worst-case conditions, AMR risk assessment, and assessment of effectiveness of the antimicrobial for the intended duration of use and across the labeled shelf life, and risk management assessment for animal-derived materials and/or botanical extracts. Companies with existing 510(k) clearances for previously unclassified devices may need to file new premarket notifications under the proposed rules demonstrating safety and effectiveness of their products by meeting these newly specified special controls.

In addition, FDA would regulate wound dressings and liquid wound washes covered by the proposed rules — including those with antimicrobials — as “devices” and not as combination products. However, FDA may require manufacturers to clarify claims that FDA views as ambiguous or prompting regulation as a drug mode of action in order to continue being treated as a medical device, or risk being classified as a combination product or as a drug.

When would the proposed rules take effect?

Under Rule 2, for newly-classified class III products, manufacturers would have 30 months from the date of rule finalization to submit PMAs; however, a notice of intent to file a PMA must be submitted within 90 days of the effective date of the final rule. If a manufacturer receives an FDA “not approvable” or denial decision rendered on a PMA, they must cease distribution of devices immediately, if the proposed rules are finalized. In such circumstances, to resume distribution, these manufacturers must receive PMA approval for their devices.

For newly-classified class II products, manufacturers of existing commercially distributed products will very likely need to file a new 510(k) notice, and demonstrate compliance with newly established applicable special controls, within six months of the effective date of the final rule unless the manufacturer has already provided similar or applicable data to FDA in prior 510(k) Notices. Under the proposed rules, compliance with special controls must be publicly stated in the product’s 510(k) Summary, which will be posted in FDA’s public-facing database.

Further considerations

The proposed new framework supports greater regulation over medical devices that contain antimicrobial substances, even if those substances are present only for preservative purposes, due to the perceived risk to patients and heightened concern over increased antimicrobial resistance.

Manufacturers of wound care products incorporating antimicrobials or other chemicals should conduct an analysis of their product(s) to assess whether they may be impacted by the proposed rules and further, the regulatory status under the proposed rules to determine whether their current marketing authorization is sufficient and the extent to which additional action would be required to comply with the proposed special controls.

In addition, many companies may be compelled to revise their products’ labeling and re-evaluate current marketing claims or risk having their products regulated as combination products or drugs. For example, the proposed rules specifically discuss the historic treatment of wound dressings and liquid wound washes containing antimicrobials as combination products if the products were “intended for wound management” or included claims that the device “may reduce the risk of infection.” The proposed rules strongly encourage manufacturers to update their products’ labeling to clarify such “wound management” or “risk of infection” reduction claims — and other claims as well — or risk enforcement action for non-compliance with the special controls associated with the proposed rules and further increased regulatory oversight. Manufacturers that fail to update their products’ labeling to clarify these types of claims may unexpectedly find their products regulated as combination products or drugs, and bear the associated regulatory burden of those distinctions.

Last, in cases of devices with high AMR concern antimicrobials, the proposed rules would classify these products as class III devices and require PMA submissions and approvals. Companies currently marketing 510(k)-cleared unclassified devices containing such antimicrobials will need to carefully evaluate their manufacturing processes, controls, labeling, and data to prepare PMA submissions, with PMA-specific user fees, for these previously cleared medical devices.

In sum, FDA’s proposed rules seek to address concerns surrounding antimicrobial resistance that is actually or potentially impacted by wound care products containing antimicrobials and other chemicals. The proposed rules are potentially far reaching and could alter the regulatory status of many existing products, even those that have the mere potential to select for antimicrobial resistance in indirect ways. Undoubtably, the costs (both in time and money) of revisiting the regulatory status of an existing product could be burdensome, and we anticipate a robust interest in the notice and comment process from both manufacturers and other stakeholders.

FDA is accepting comments on both proposed rules through February 28, 2024.