[Federal Register Volume 88, Number 229 (Thursday, November 30, 2023)]
[Proposed Rules]
[Pages 83774-83802]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-26209]



[[Page 83773]]

Vol. 88

Thursday,

No. 229

November 30, 2023

Part V





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Part 878





Medical Devices; General and Plastic Surgery Devices; Classification of 
Certain Solid Wound Dressings; Wound Dressings Formulated as a Gel, 
Creams, or Ointment; and Liquid Wound Washes and Effective Date of 
Requirement for Premarket Approval Applications for Certain Solid Wound 
Dressings; Wound Dressings Formulated as a Gel, Cream, or Ointment; and 
Liquid Wound Washes Containing Medically Important Antimicrobials; 
Proposed Rules

  Federal Register / Vol. 88 , No. 229 / Thursday, November 30, 2023 / 
Proposed Rules  

[[Page 83774]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 878

[Docket No. FDA-2023-N-3392]
RIN 0910-A126


Medical Devices; General and Plastic Surgery Devices; 
Classification of Certain Solid Wound Dressings; Wound Dressings 
Formulated as a Gel, Creams, or Ointment; and Liquid Wound Washes

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) are 
proposing to classify certain types of wound dressings and liquid wound 
washes containing antimicrobials and/or other chemicals (unclassified, 
preamendments devices) as solid wound dressings; wound dressings 
formulated as a gel, cream, or ointment; and liquid wound washes. FDA 
currently regulates these unclassified devices as devices requiring 
premarket notification (510(k) requirements), with the product codes 
FRO, GER, MGP, MGQ, and EFQ, but FDA intends to create new product 
codes for these proposed classifications upon finalization of this 
classification action. FDA is proposing to classify certain wound 
dressings and liquid wound washes containing antimicrobials with a high 
level of antimicrobial resistance (AMR) concern (i.e., medically 
important antimicrobials) into class III. In addition, FDA is proposing 
to classify certain wound dressings and liquid wound washes containing 
antimicrobials with a medium or low level of AMR concern and/or other 
chemicals, into class II (subject to special controls and 510(k) 
requirements).

DATES: Either electronic or written comments on the proposed rule must 
be submit by February 28, 2024.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of February 28, 2024. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2023-N-3392 for ``Medical Devices; General and Plastic Surgery 
Devices; Classification of Certain Solid Wound Dressings; Wound 
Dressings Formulated as a Gel, Creams, or Ointment; and Liquid Wound 
Washes.'' Received comments, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Brandon Kitchel, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 4626, Silver Spring, MD 20993-0002, 301-
796-6055, [email protected].

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Acronyms Commonly Used Acronyms in This 
Document
III. Background
    A. Need for the Regulation
    B. Terminology
    C. FDA's Current Regulatory Framework
    D. History of This Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Scope/Applicability

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    B. Device Description
    C. Risks to Health and Public Health Benefits
    D. Proposed Classification and FDA's Findings
VI. Proposed Effective/Compliance Dates
    A. Devices That Are Proposed To Be Classified Into Class III
    B. Devices That Are Proposed To Be Classified Into Class II
VII. Preliminary Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to classify certain unclassified, preamendments 
wound dressings and liquid wound washes containing antimicrobials and/
or other chemicals into three separate classification regulations: (1) 
solid wound dressings; (2) wound dressings formulated as a gel, cream, 
or ointment; and (3) liquid wound washes. A list of examples of 
antimicrobials and a list of categories and examples of other chemicals 
contemplated by this proposed rule are found in table 2 and table 3, 
respectively. For solid wound dressings, the intended use is to cover 
and protect a wound, to absorb exudate, and to maintain appropriate 
moisture balance within the wound. For wound dressings formulated as a 
gel, cream, or ointment, the intended use is to maintain appropriate 
moisture balance within the wound. For liquid wound washes, the 
intended use is to mechanically irrigate and physically remove debris 
from external wounds. It is also to moisten solid wound dressings to 
maintain appropriate moisture balance within the dressing.
    FDA currently regulates these unclassified devices \1\ as devices 
requiring premarket notification (510(k) requirements), with the 
product codes FRO, GER, MGP, MGQ, and EFQ.\2\ FDA intends to create new 
product codes for these proposed classifications upon finalization of 
this classification action.\3\ This proposed classification is based, 
in part, on the recommendations of multiple General and Plastic Surgery 
Devices Panel meetings (held on November 27, 1998 (Ref. 1), August 25 
and 26, 2005 (Ref. 2), and September 20 and 21, 2016 (Ref. 3)) 
regarding the classification of wound dressings, public comments 
received on such recommendations, FDA's experience with these wound 
dressings and liquid wound washes, and other available information.
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    \1\ We refer to these products as devices because of their 
device mode of action, although, as noted later in the document, 
many of the products with wound management claims, based on a broad 
interpretation of such claims, have previously been generally 
identified as combination products. As explained later in the 
document, one of the purposes of this rulemaking is to clarify the 
intended uses of these products for classification purposes, based 
on the recommendations of the General and Plastic Surgery Devices 
Panel, by proposing not to include broad ``wound management'' claims 
in product labeling and be clarified to reflect the specific 
functions discussed in this document (e.g., ``to protect and cover a 
wound''). Products that continue to have broad wound management 
claims, which may be unclear or misleading or indicate an objective 
intent outside of the clarified intended uses, will not be covered 
by and benefit from this proposed rulemaking and classification. 
After this proposed rule is finalized and the classification becomes 
effective, such products could be subject to a different type of 
marketing authorization, depending on the product claims. For 
example, products containing antimicrobials that make certain wound 
managements claims may be considered combination products or drugs 
and regulated as such.
    \2\ FDA's Center for Devices and Radiological Health (CDRH) uses 
product codes to help categorize and assure consistent regulation of 
medical devices. A product code consists of three characters that 
are assigned at the time a product code is generated and is unique 
to a product type. The three characters carry no other significance 
and are not an abbreviation.
    \3\ See ``Medical Device Classification Product Codes--Guidance 
for Industry and FDA Staff,'' available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff.
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    As discussed further in this preamble, FDA believes that with 
clarification of intended use claims, wound dressings and liquid wound 
washes subject to this proposed rule, including those with 
antimicrobials, should be regulated only as ``devices'' and not as 
combination products.\4\ These products, though perhaps previously 
identified as combination products, are within the scope of this 
classification. Additionally, wound dressings and liquid wound washes 
that do not contain a component that achieves a primary intended 
purpose of the product through chemical action within or on the body 
are considered devices, even if these products contain components that 
are regulated as drugs in other contexts.\5\ Further discussion of 
these products is included in the intended use(s) section under section 
V.B.
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    \4\ See definition of combination product at 21 CFR 3.2(e).
    \5\ For information on the classification of products as drugs, 
devices, or biological products, please see the guidance 
``Classification of Products as Drugs and Devices and Additional 
Product Classification Issues,'' available at https://www.fda.gov/media/80384/download.
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    The proposed classification for solid wound dressings is intended 
to be a split classification. FDA is proposing to classify solid wound 
dressings containing medically important antimicrobials acting as 
protectants (Ref. 4) \6\ into class III due to their high level of 
antimicrobial resistance (AMR) \7\ concern (as discussed in Section 
III.B Terminology). Table 1 of the World Health Organization's (WHO) 
2018 publication ``Critically Important Antimicrobials for Human 
Medicine: 6th Edition'' (Ref. 4) has a list of all classes of medically 
important antimicrobials. For the purposes of this proposed rule, 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). FDA is proposing this classification as FDA believes that 
insufficient information exists to determine that general controls and 
special controls would provide reasonable assurance of safety and 
effectiveness for such wound dressings, and these dressings present a 
potential unreasonable risk of illness or injury. FDA is proposing, by 
proposed order published elsewhere in this issue of the Federal 
Register, to require the filing of premarket approval applications 
(PMAs) for such devices.
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    \6\ For the purposes of this proposed rule and classification 
action, medically important antimicrobials are antimicrobial drugs 
that are important for therapeutic use in humans and associated with 
a high level of AMR concern. WHO has worked to categorize medically 
important antimicrobials based on the level of importance these 
drugs play in human medicine (https://www.who.int/publications/i/item/9789241515528). While the Agency has made similar efforts to 
categorize medically important antimicrobials, such as the work to 
address the use of medically important antimicrobial drugs in food-
producing animals (https://www.fda.gov/media/172347/download?attachment), the current classification efforts do not 
attempt to further stratify the degree of importance of these 
antimicrobial drugs.
    \7\ For the purposes of this proposed rule and classification 
action, antimicrobial resistance is the ability of a microorganism 
(e.g., bacteria or fungi) to resist the effects of an antimicrobial.
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    FDA is proposing to classify solid wound dressings containing 
antimicrobials that are acting as protectants with medium or low level 
of AMR concern and/or other chemicals into class II (special controls). 
Please see Section III.B Terminology for more information on 
antimicrobials that are acting as protectants and on other chemicals. 
Antimicrobials acting as protectants are used to reduce microbial 
growth within the dressing while in use or to provide an antimicrobial 
barrier to microbial penetration through the dressing. FDA is proposing 
this classification action based on the determination that general 
controls

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alone are not sufficient to provide reasonable assurance of the safety 
and effectiveness of these solid wound dressings, and there is 
sufficient information to establish special controls, in combination 
with general controls, to provide such assurance.
    Similarly, FDA is proposing a split classification for wound 
dressings formulated as a gel, cream, or ointment. FDA is proposing to 
classify wound dressings formulated as a gel, cream, or ointment 
containing medically important antimicrobials acting as preservatives 
into class III due to their high level of AMR concern. FDA is proposing 
this classification as FDA believes that insufficient information 
exists to determine that general controls and special controls would 
provide reasonable assurance of safety and effectiveness for such wound 
dressings and that these dressings present a potential unreasonable 
risk of illness or injury. FDA is proposing, by proposed order 
published elsewhere in this issue of the Federal Register, to require 
the filing of PMAs for such devices.
    FDA proposes to classify wound dressings formulated as a gel, 
cream, or ointment containing antimicrobials acting as preservatives 
(as discussed in Section III.B Terminology) with medium or low AMR risk 
and/or other chemicals into class II. Antimicrobials acting as 
preservatives are used to maintain shelf life for a nonsterile, single-
use wound dressing or a multiple-use wound dressing for single patient 
use only with compromised sterility after opening and using for a 
defined period. FDA is proposing this action based on the determination 
that general controls alone are not sufficient to provide reasonable 
assurance of the safety and effectiveness of these wound dressings, and 
there is sufficient information to establish special controls, in 
combination with general controls, to provide such assurance.
    FDA is also proposing a split classification for liquid wound 
washes. FDA is proposing to classify liquid wound washes containing 
medically important antimicrobials acting as preservatives into class 
III due to their high level of AMR concern. FDA is proposing this 
classification as FDA believes that insufficient information exists to 
determine that general controls and special controls would provide 
reasonable assurance of safety and effectiveness for such liquid wound 
washes and these washes present a potential unreasonable risk of 
illness or injury. FDA is proposing, by proposed order published 
elsewhere in this issue of the Federal Register, to require the filing 
of PMAs for such devices.
    FDA is proposing to classify liquid wound washes containing 
antimicrobials acting as preservatives with medium or low level AMR 
concern and/or other chemicals into class II. FDA is proposing this 
classification action based on the determination that general controls 
alone are not sufficient to provide reasonable assurance of the safety 
and effectiveness of these wound washes and that there is sufficient 
information to establish special controls, in combination with general 
controls, to provide such assurance. Additionally, if this proposed 
rule is finalized, FDA plans to publish a notice in the Federal 
Register announcing its intent to exempt liquid wound washes containing 
water or 0.9 percent saline only, which do not contain antimicrobials, 
other chemicals, or animal-derived materials, from the requirements of 
submitting a 510(k), subject to certain limitations, under the Federal 
Food, Drug, and Cosmetic Act (FD&C Act).

B. Summary of the Major Provisions of the Proposed Rule

    This rule proposes to classify certain of the following 
unclassified, preamendments wound dressings and liquid wound washes 
containing antimicrobials and/or other chemicals: (1) solid wound 
dressings; (2) wound dressings formulated as a gel, cream, or ointment; 
and (3) liquid wound washes. The proposed rule, if finalized, would 
establish the identifications and classifications for certain solid 
wound dressings; wound dressings formulated as a gel, cream, or 
ointment; and liquid wound washes.
    The proposed classification action proposes to classify into class 
III and require the filing of a PMA for wound dressings and liquid 
wound washes (i.e., solid wound dressings; wound dressings formulated 
as a gel, cream, or ointment; and liquid wound washes) containing 
medically important antimicrobials used for preservative or protectant 
purposes. This proposed classification action proposes also to classify 
solid wound dressings containing antimicrobials acting as protectants 
with a medium or low level of AMR concern and/or other chemicals into 
class II. Wound dressings formulated as a gel, cream, or ointment and 
liquid wound washes containing antimicrobials acting as preservatives 
with a medium or low level of AMR concern and/or other chemicals are 
being proposed for classification into class II. These certain class II 
wound dressings and liquid wound washes would be classified with 
special controls that require specific information relating to 
performance testing and technical specifications, specific labeling 
requirements, and other requirements to mitigate the risks to health 
and demonstrate a reasonable assurance of safety and effectiveness, in 
combination with general controls.
    If this proposed rule is finalized, FDA plans to exempt from 510(k) 
certain liquid wound washes containing water or 0.9 percent saline 
only, which do not contain antimicrobials, other chemicals, or animal-
derived materials, subject to certain limitations. An exemption from 
the requirement of 510(k) does not mean that the device type is exempt 
from any other statutory or regulatory requirements unless such 
exemption is explicitly provided by order or regulation.

C. Legal Authority

    The Agency is proposing this classification under the authority of 
section 301 of the FD&C Act (21 U.S.C. 301). Specifically, the relevant 
authority related to the proposed classification includes sections 
513(a) through (d) of the FD&C Act regarding device classes, 
classification, and panels; section 515 of the FD&C Act regarding PMAs; 
and section 701(a) of the FD&C Act (21 U.S.C. 371(a)).

D. Costs and Benefits

    If the proposed rule is finalized, society may experience welfare 
gains from reductions in AMR due to the rule. These welfare gains would 
be in the form of decreased mortality, morbidity, and medical costs. 
Unfortunately, the magnitude of these potential benefits is difficult 
to forecast, and we do not quantify these impacts in the analysis.
    The quantifiable benefits of the proposed rule, if finalized, 
accrue to manufacturers of wound dressings and liquid wound washes and 
FDA. These benefits are the result of clarifications in the 510(k) 
submission process, specifically defined regulatory classification, and 
published special controls. This additional clarity in requirements 
should result in fewer additional information submissions to FDA.
    We estimate annualized cost savings ranging from approximately 
$1.12 million to $6.31 million at a 3 percent discount rate, and 
approximately $1.14 million to $6.42 million at a 7 percent discount 
rate. Our primary annualized estimates are approximately $2.66 million 
at a 3 percent discount rate and $2.71 million at a 7 percent discount 
rate. The primary estimates of the present value of total cost savings 
in the 10 years following any final rule that may be issued based on 
this proposed

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rule are $24.55 million at a 3 percent rate of discount and $19.02 
million at a 7 percent rate of discount.
    The costs of the proposed rule, if finalized, are associated with 
costs to industry for reading and understanding the rule, preparing and 
submitting PMAs, and other costs related to the PMA process and 
maintaining the class III designation. FDA also incurs costs from 
reviewing PMAs, annual and supplemental reports, and inspection 
activities. When annualized over a period of 10 years, we estimate 
these costs range from approximately $0.72 million to $1.25 million at 
a 3 percent discount rate, and approximately $0.65 million to $1.17 
million at a 7 percent discount rate. Our primary annualized estimates 
are approximately $0.92 million at a 3 percent discount rate and $0.85 
million at a 7 percent discount rate. The primary estimates of the 
present value of total costs in the 10 years following any final rule 
that may be issued based on the proposed rule are approximately $7.23 
million at a 3 percent discount rate and $6.48 million at a 7 percent 
discount rate.

II. Table of Abbreviations/Acronyms Commonly Used Acronyms in This 
Document

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     Abbreviation/acronym                     What it means
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510(k)........................  Premarket Notification.
AMR...........................  Antimicrobial Resistance.
CDC...........................  Centers for Disease Control and
                                 Prevention.
CDRH..........................  Center for Devices and Radiological
                                 Health.
CFR...........................  Code of Federal Regulations.
FD&C Act......................  Federal Food, Drug, and Cosmetic Act.
FDA...........................  Food and Drug Administration.
FRO...........................  The current product code for
                                 unclassified, preamendments wound
                                 dressings containing antimicrobials and/
                                 or other chemicals.\8\
GER...........................  The product code for unclassified,
                                 preamendments devices known as external
                                 gauze with drug/biologic/animal source
                                 material.\9\
MGP...........................  The product code for unclassified,
                                 preamendments devices known as
                                 occlusive wound and burn dressing.\10\
MGQ...........................  The product code for unclassified,
                                 preamendments devices known as wound
                                 and burn hydrogel dressing with drug
                                 and/or biologic.\11\
EFQ...........................  The product code for unclassified,
                                 preamendments devices known as internal
                                 gauze and sponge.\12\
HHS...........................  Department of Health and Human Services.
PHMB..........................  Polyhexamethylene Biguanide.
PMA...........................  Premarket Approval Application.
OIRA..........................  Office of Information and Regulatory
                                 Affairs.
U.S...........................  United States.
WHO...........................  World Health Organization.
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III. Background 
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    \8\ Some products cleared under this product code are within 
scope for this proposed rule and proposed classification action. 
Other products under this product code are not within scope of this 
proposed rule and will be addressed via a separate classification 
action.
    \9\ Ibid.
    \10\ Ibid.
    \11\ Ibid.
    \12\ Ibid.
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A. Need for the Regulation

    Currently, certain solid wound dressings; wound dressings 
formulated as a gel, cream, or ointment; and liquid wound washes that 
contain antimicrobials and/or other chemicals are unclassified devices 
subject to premarket notification (510(k)) under section 510(k) of the 
FD&C Act (21 U.S.C. 360(k)). Until an unclassified device type has been 
formally classified by regulation, and such formal classification may 
or may not require a different type of premarket submission depending 
on the classification, marketing of new devices within this device type 
requires FDA clearance of a 510(k). As described below, these devices 
have generally been subject to premarket review through the 510(k) 
pathway and have been cleared for marketing if their intended use and 
technological characteristics are ``substantially equivalent'' to 
devices that were in commercial distribution prior to the passage of 
the Medical Device Amendments on May 28, 1976.
    Wound dressings and liquid wound washes subject to this proposed 
rule and classification action can be subcategorized into three broad 
categories based on their physical form, including: (1) solid wound 
dressings; (2) gels, creams, or ointments; and (3) liquid wound washes. 
Irrespective of physical form, these wound dressings and liquid wound 
washes have typically been indicated for use on a variety of acute 
(e.g., traumatic wounds, surgical wounds, etc.) and chronic (e.g., 
venous stasis ulcers, diabetic foot ulcers, arterial ulcers, etc.) 
wounds. Solid wound dressings have also been cleared with uses such as 
to provide or support a moist wound environment, absorb wound exudate, 
and protect against external contamination. Wound gels, ointments, and 
creams have been cleared to provide or support a moist wound 
environment. Liquid wound washes have been cleared to rinse or irrigate 
a wound and to remove foreign material, such as debris and wound 
exudate. Refer to table 1 for a tabular overview of the wound dressings 
and liquid wound washes within the scope of this proposed 
classification action.

[[Page 83778]]



Table 1--Proposed Classification of the Wound Dressings and Liquid Wound Washes Containing Antimicrobials and/or
                                                 Other Chemicals
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                                                                    Wound dressings
                                        Solid wound dressings     formulated as a gel,
                                              containing           cream, or ointment
                                        antimicrobials and/or          containing          Liquid wound washes
       Proposed classification             other chemicals       antimicrobials and/or     (Proposed new 21 CFR
                                         (Proposed new 21 CFR       other chemicals             878.4019)
                                              878.4016)           (Proposed new 21 CFR
                                                                       878.4017)
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Class III (Proposing to require the    Products containing      Products containing      Products containing
 filing of a PMA).                      medically important      medically important      medically important
                                        antimicrobials acting    antimicrobials acting    antimicrobials acting
                                        as protectants           as preservatives         as preservatives
                                        (Proposed Sec.           (Proposed Sec.           (Proposed Sec.
                                        878.4016(b)(1)).         878.4017(b)(1)).         878.4019(b)(1)).
Class II (Special Controls + General   Products containing      Products containing      Products containing
 Controls) Subject to 510(k)            antimicrobials acting    antimicrobials acting    antimicrobials acting
 Requirements.                          as protectants with a    as preservatives with    as preservatives with
                                        medium or low level of   a medium or low level    a medium or low level
                                        AMR concern, and/or      of AMR concern, and/or   of AMR concern, and/or
                                        other chemicals          other chemicals          other chemicals
                                        (Proposed Sec.           (Proposed Sec.           (Proposed Sec.
                                        878.4016(b)(2)).         878.4017(b)(2)).         878.4019(b)(2)).
----------------------------------------------------------------------------------------------------------------

    Outside of the scope for this rulemaking, FDA has previously 
classified certain wound dressings (which have similar intended uses as 
the products in scope for this proposed rule, but do not contain 
antimicrobials or other chemicals) as class I and exempt from 510(k) 
requirements (see 21 CFR 878.4014, 878.4018, 878.4020, and 878.4022). 
FDA has also previously determined wound dressings intended to 
accelerate the normal rate of wound healing that serve as a replacement 
for full-thickness skin grafting (e.g., artificial skin substitute) or 
treat full-thickness (i.e., third degree) burns to be class III medical 
devices. An example of a class III wound dressing is the Integra 
Omnigraft Dermal Regeneration Matrix that was approved through PMA 
P900033.\13\ In addition to wound care products regulated by Center for 
Devices and Radiological Health (CDRH), the Center for Drug Evaluation 
and Research regulates certain drugs used in wound care, such as silver 
sulfadiazine cream indicated for the prevention and treatment of wound 
sepsis,\14\ and the Center for Biologics Evaluation and Research 
regulates certain wound care products, such as the OrCel Bilayered 
Cellular Matrix composed of human allogeneic skin cells (PMA 
P010016).\15\
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    \13\ FDA Premarket Approval, Integra Omnigraft Dermal 
Regeneration Matrix, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P900033S042.
    \14\ Drugs at FDA, Silver Sulfadiazine Cream, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017381s053lbl.pdf.
    \15\ FDA Premarket Approval, OrCel\TM\ (Bilayered Cellular 
Matrix), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010016.
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    Wound dressings and liquid wound washes containing antimicrobials 
and/or other chemicals play a critical role in wound care for patients 
in the United States. Human skin wounds pose substantial risks to 
patients and increasing challenges to the U.S. public health (Ref. 5). 
The prevalence rate for chronic, nonhealing wounds is ~2 percent of the 
general population (Ref. 6). This prevalence rate is similar to that of 
heart failure, but unlike heart failure, little is known regarding the 
outcome of these patients or the comparative effectiveness of the 
treatment they receive (Ref. 7). An aging population and its requisite 
medical interventions, the continuing rise in diabetes and obesity, and 
the increase in traumatic wounds all translate to large increases in 
skin wounds needing treatment (Refs. 6 and 8). Patients with the 
hardest to heal wounds include those with diabetes, obesity, sickle 
cell ulcers, vasculitis, and scleroderma (Refs. 6 and 8).
    The cost of wound care in the United States alone exceeds $50 
billion annually (Refs. 9-12). It is estimated that chronic, nonhealing 
wounds affect approximately 6.5 million people annually in the United 
States (Ref. 13). Often, these wounds become infected, interrupting and 
delaying wound healing and leading to increased treatment times, 
suffering, risk of severe complications, and expenses (Ref. 14). The 
annual wound care products market is expected to reach $22 billion by 
2024, which demonstrates the magnitude of their impact on public health 
(Ref. 15).

B. Terminology

1. Medically Important Antimicrobial
    For the purposes of this proposed rule and this classification 
action, the term ``medically important'' antimicrobial refers to an 
antimicrobial drug that is important for therapeutic use in humans 
(Ref. 16). Table 1 of the WHO's 2018 publication entitled ``Critically 
Important Antimicrobials for Human Medicine: 6th Edition'' (Ref. 4) has 
a list of all classes of medically important antimicrobials. For the 
purposes of this proposed rule and classification action, 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).
2. High, Medium, and Low AMR Concern
    For the purposes of this proposed rule and this classification 
action, the level of AMR concern has been defined based on the 
following antimicrobial characteristics:
     High-level of AMR concern results from wound dressings and 
liquid wound washes that contain a medically important antimicrobial as 
these products may directly contribute to the development and spread of 
organisms in the patient that are resistant to medically important 
antimicrobials, potentially further limiting a clinician's therapeutic 
options.
     Medium-level AMR concern results from wound dressings and 
liquid wound washes that contain a nonmedically important antimicrobial 
which may indirectly select for organisms with medically important 
antimicrobial resistance mechanisms via coselection mechanisms such as 
coresistance and cross-resistance.\16\
---------------------------------------------------------------------------

    \16\ Coresistance occurs when there are different resistance 
determinants present on the same genetic element. Cross-resistance 
occurs when the same genetic determinant is responsible for 
resistance to multiple types of antimicrobials, such as antibiotics 
and metals. See Baker-Austin C., M. Wright, R. Stepanauskas, et al., 
``Co-Selection of Antibiotic and Metal Resistance,'' Trends in 
Microbiology, 14(4), 2006. Available at https://www.cell.com/trends/microbiology/fulltext/S0966-842X(06)00051-5.
---------------------------------------------------------------------------

     Low-level AMR concern results from wound dressings and 
liquid wound washes that contain a nonmedically important antimicrobial 
which lacks the ability to coselect for organisms with medically 
important antimicrobial resistance mechanisms. As microbial resistance 
mechanisms are constantly evolving, the categorization of low level of 
AMR concern for a particular antimicrobial may be upgraded to a medium 
level of AMR concern based on future emerging resistance information, 
such as evidence of coresistance or cross-resistance to medically 
important antimicrobials.

[[Page 83779]]

3. Antimicrobials as Preservatives or Protectants
    To be within the scope of this proposed rule and classification 
action, 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) a preservative or (2) a protectant 
of the product.
    For the purposes of this proposed rule and proposed classification 
action, an antimicrobial is considered a preservative when added to 
wound dressings formulated as a gel, cream, or ointment and liquid 
wound washes solely to prevent or reduce contamination or deterioration 
thereof while in its packaging during shelf storage.\17\ This 
preservative role helps maintain product integrity and safety 
throughout a defined shelf life and/or use life. A preservative may be 
included in wound dressings formulated as a gel, cream, or ointment or 
liquid wound washes when there is a scientific need for the inclusion 
of the preservative. For example, preservatives may be needed when the 
product is provided to the user nonsterile, or when the product is 
provided as a sterile single-patient, multiple-use product which 
contains a preservative to reduce microbial growth in the product over 
a specified period after the sterile seal has been broken. In these 
situations, the preservative may be used to maintain sufficiently low 
bioburden and to prevent or retard deterioration of the product prior 
to application of the wound dressings formulated as a gel, cream, or 
ointment or liquid wound washes.
---------------------------------------------------------------------------

    \17\ Based on FDA's experience, in rare occasions, an 
antimicrobial may be added to a sterile, single-use amorphous wound 
dressing as a manufacturing aid to reduce bioburden prior to the 
manufacturing of the final, finished device.
---------------------------------------------------------------------------

    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 this 
proposed rule. As discussed later, other uses, such as delivery of 
antimicrobials to the wound, suggest an intent for the treatment of 
infection, which is generally achieved through chemical action within 
or on the wound and may not fall under CDRH's jurisdiction. 
Additionally, as solid wound dressings are generally provided as 
sterile, single-use products, the inclusion of antimicrobial 
preservatives in solid wound dressings would not be necessary.
    For the purposes of this proposed rule and proposed classification 
action, an antimicrobial is considered a protectant when added to a 
solid wound dressing to prevent or reduce contamination or 
deterioration of the dressing while in contact with the wound. This 
protectant role supports the use of solid wound dressings (i.e., to 
cover and protect a wound, absorb exudate, and maintain appropriate 
moisture balance within the wound) throughout a defined use life. A 
protectant may be included in solid wound dressings when there is a 
scientific need for the inclusion of the protectant (e.g., solid wound 
dressings which may be applied to a wound for a period of multiple days 
and the dressing may be susceptible to microbial colonization and 
biofouling). FDA is unaware of a clinical need for including a 
protectant in wound dressings formulated as a gel, cream, or ointment 
or liquid wound washes, as an application of these products is not 
designed to remain on the body for sufficient time to justify clinical 
concern with microbial colonization of the product. Refer to table 2 
for a tabular overview of examples of antimicrobials that are within 
the scope of this proposed classification action.

 Table 2--List of Examples of Antimicrobials * That Are Within the Scope
 of the Proposed Rule and the Proposed Classification Action for Certain
                 Wound Dressings and Liquid Wound Washes
------------------------------------------------------------------------
                               Antimicrobials with   Antimicrobials with
  Antimicrobials with high-     medium-level AMR        low-level AMR
     level AMR concern *             concern               concern
------------------------------------------------------------------------
Polymyxin B.................  Silver..............  Parabens.
Silver sulfadiazine.........  Zinc................  Hypochlorous acid.
Bacitracin..................  Copper..............  Peroxide.
                              Chlorhexidine.......  Polyhexamethylene
                                                     biguanide (PHMB).
                              Benzalkonium          Iodine.
                               chloride.
------------------------------------------------------------------------
* As identified in the WHO's ``Critically Important Antimicrobials for
  Human Medicine,'' Polymyxin B falls within the Polymyxcin class of
  medically important antimicrobials, Silver sulfadiazine falls within
  the Sulfonamide class of medically important antimicrobials, and
  Bacitracin falls within the Cyclic polypeptide class of medically
  important antimicrobials.

4. Other Chemicals
    Wound dressings and liquid wound washes may contain other 
chemicals. Categories of other chemicals are wound protectants, honey, 
synthetic peptides, or botanical extracts. For the purposes of this 
proposed rule and proposed classification action, these ingredients are 
grouped as ``other chemicals'' and are only used to contribute to the 
uses of wound dressings and liquid wound washes by physical means (see 
table 3). Ingredients that achieve their primary intended purposes 
through chemical action would not fall under ``other chemicals'' for 
purposes of this proposed rule and proposed classification action and 
are therefore outside its scope.
     Wound protectants.\18\ Wound dressings may contain wound 
protectants that provide a physical barrier to the external environment 
and help maintain moisture balance within the wound.
---------------------------------------------------------------------------

    \18\ Ingredients in the ``wound protectant'' category of ``other 
chemicals'' overlap in some cases with active ingredients included 
in the over-the-counter (OTC) drug product monograph for ``skin 
protectant drug products,'' which was codified in 21 CFR part 347. 
These provisions now appear in the final order for skin protectant 
drug products under section 505G of the FD&C Act (21 U.S.C. 355g), 
which was added by the Coronavirus Aid, Relief, and Economic 
Security Act, Public Law 116-136, 134 Stat. 281 (2020). Orders for 
OTC monograph drugs can be found at https://dps.fda.gov/omuf. Under 
section 3621 of the Food and Drug Omnibus Reform Act of 2022, Public 
Law 117-328, 136 Stat 4459, which added section 503(h) to the FD&C 
Act (21 U.S.C. 353(h), products meeting the definition of ``OTC 
monograph drug'' under section 744L of the FD&C Act (21 U.S.C. 379j-
71), including certain skin protectants, are deemed to be drugs. 
When intended for marketing in accordance with this proposed rule, 
however, products containing these ingredients, which may be 
included as ``wound protectants,'' would not be considered OTC 
monograph drugs or otherwise considered drug constituent parts. 
Please note that to be considered a ``wound protectant'' in 
accordance with this proposed rule and classification action, an 
ingredient cannot achieve its primary intended purpose through 
chemical action. Products containing such ingredients are outside 
the scope of this proposed rule and classification action.

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[[Page 83780]]

     Honey. Wound dressings may contain honey, which helps 
maintain moisture balance within the dressing.
     Synthetic Peptides. Wound dressings may include synthetic 
peptides, which are used to create a fibrous scaffold and provide 
physical structure to the wound dressing.
     Botanical extracts. Wound dressings may contain botanical 
extracts, which have such uses as to help maintain moisture balance 
within the dressing (e.g., as moisturizers, humectants, or emollients) 
and contribute to the physical structure of the dressing (e.g., as 
thickeners, emulsifiers, or stabilizers). A botanical extract is often 
a complex mixture of vegetable matter obtained from plants, algae, 
macroscopic fungi, and/or combinations of these species. For the 
purposes of this proposed rule, plant-derived materials that are highly 
purified (e.g., cellulose) or well-characterized (e.g., cotton) are not 
considered as other chemicals.

 Table 3--Categories and Examples of Other Chemicals That Are Within the
  Scope of the Proposed Rule and the Proposed Classification Action for
                         Certain Wound Dressings
------------------------------------------------------------------------
     Categories of other  chemicals         Examples of other chemicals
------------------------------------------------------------------------
Wound Protectants.......................  Petrolatum, mineral oil, cod
                                           liver oil, white petrolatum,
                                           lanolin, glycerin,
                                           dimethicone, lanolin,
                                           allantoin, zinc oxide,
                                           aluminum hydroxide, calamine,
                                           sodium bicarbonate, zinc
                                           acetate, zinc carbonate.
Honey...................................  Manuka honey, buckwheat honey.
Synthetic Peptides......................  RADA16 (RADARADARADARADA)
                                           peptide, self-assembling
                                           peptides.
Botanical Extracts......................  Olive oil, grape seed extract,
                                           aloe, lavender, tea tree oil,
                                           vegetable oil, shea butter,
                                           sesame oil.
------------------------------------------------------------------------

5. Animal-Derived Materials
    Solid wound dressings, wound dressings formulated as a gel, cream, 
or ointment, and liquid wound washes may also contain animal-derived 
materials. Generally, these animal-derived dressing materials are 
degradable, but may also contain nondegradable materials. This proposed 
rule excludes wound dressings and liquid wound washes containing 
animal-derived materials without the presence of antimicrobials or 
other chemicals, as these products are currently regulated as a 
distinct category under the product code KGN. More information 
regarding the categories of wound dressings and liquid wound washes 
that are outside the scope of this rulemaking is included in Section 
V.A Scope/Applicability of this proposed rule.
6. Antimicrobial Resistance
    In the past century, the discovery and implementation of medically 
important antimicrobials (e.g., antibiotics) have revolutionized modern 
medicine, making once lethal infections readily treatable and extending 
the average human lifespan by 23 years (Ref. 17). Unfortunately, we now 
live in an era when people are dying from untreatable infections 
because of the emergence and spread of AMR--the ability of 
microorganisms (e.g., bacteria and fungi) to resist the effects of an 
antimicrobial. The development and spread of AMR are widely recognized 
as a serious public health threat. According to the U.S. Centers for 
Disease Control and Prevention (CDC), drug-resistant bacteria cause 
more than 35,000 deaths and 2.8 million illnesses each year in the 
United States (Ref. 18). In addition to the impact on patient morbidity 
and mortality, AMR infections require prolonged and costlier 
treatments, with estimates suggesting the U.S. economic impact to be 
around $55 billion per year (Ref. 19).
    With a lack of novel antibiotics being developed, it is critical to 
preserve the effectiveness of our current antimicrobial therapeutic 
options. Based on the 2016 National Quality Partners' ``Antibiotic 
Stewardship in Acute Care: A Practical Playbook'' (Ref. 20), 20 percent 
to 50 percent of antibiotics prescribed in U.S. acute care hospitals 
are unnecessary or inappropriate, and this overuse and misuse of 
medically important antimicrobials have contributed to the cultivation 
of an abundance of drug-resistant organisms that are becoming 
increasingly difficult to treat. Changes to clinical practice patterns 
to promote appropriate use of antimicrobial drugs are essential, and in 
2014, the CDC called on all U.S. hospitals to implement antimicrobial 
stewardship programs (Ref. 21) that measure and improve how 
antimicrobials are prescribed and used by patients. Additionally, 
public health agencies in the Department of Health and Human Services, 
including FDA, are engaged in efforts to promote antimicrobial 
stewardship practices to maintain a more judicious use of 
antimicrobials and curb the spread of AMR (Ref. 22).
    While an antimicrobial is effective when applied at an appropriate 
concentration, this effectiveness is only exhibited on a limited 
segment of the microbial world. Some species of bacteria are naturally 
resistant to a given antimicrobial, while others may eventually acquire 
resistance (e.g., via random mutation or acquisition of a resistance 
gene) (Ref. 23). After decades of antimicrobial exposure, 
microorganisms have developed a vast array of antimicrobial resistance 
mechanisms, including the expression of hydrolytic enzymes, activation 
of efflux pump systems, and the alteration of cell wall permeability 
(Ref. 23). Many antimicrobial resistance genes are found on plasmids, 
which not only play an integral role in the horizontal transfer of 
resistance between organisms, but can also stack multiple resistance 
genes together on a single mobile element (Ref. 24). As a result, many 
of today's hospital-acquired infections involve bacteria that are 
resistant to multiple classes of antimicrobials, which may include both 
medically important antimicrobials along with other broad-spectrum 
antimicrobials (e.g., metals, biguanides, quaternary ammonium 
compounds) (Refs. 25 and 26).
    Although all antimicrobial resistance is important, additional 
consideration is needed based on the level of importance a particular 
antimicrobial plays in human medicine and the availability of other 
therapeutic options to treat or mitigate specific infections (Refs. 6, 
27-29). While medically important antimicrobials (e.g., antibiotics) 
are the focal point of antimicrobial stewardship practices and 
resistance classification efforts, there are other antimicrobials that 
are routinely utilized in healthcare, such as antiseptics (which 
inhibit or kill microorganisms in or on living tissue, such as hand 
washes) and disinfectants (which inhibit or kill microorganisms on 
inanimate objects or surfaces) (Ref. 30).
    Historically, wound dressings and liquid wound washes have utilized 
a wide range of antimicrobials as preservatives or protectants, each 
with a varying degree of AMR information

[[Page 83781]]

detailed in the literature. When evaluating the level of AMR concern 
associated with antimicrobials used as preservatives or protectants in 
wound dressings and liquid wound washes, the probable benefit of the 
wound dressing and liquid wound wash should outweigh the probable risk 
of contributing to the development and spread of resistance, and, 
particularly, resistance to medically important antimicrobials. As 
such, FDA is proposing a risk-based approach for assessing the level of 
AMR concern (high, medium, or low) associated with wound dressings and 
liquid wound washes containing antimicrobials, as described in Section 
III.B Terminology.
    Based on feedback from the 2016 Panel, a high level of AMR concern 
is associated with the use of medically important antimicrobials (e.g., 
antibiotics), as this may present an unreasonable risk of illness or 
injury by directly contributing to the selection of organisms in the 
patient that are resistant to medically important antimicrobials, 
potentially further limiting a clinician's therapeutic options. 
Likewise, it is important to understand and evaluate the potential for 
an antimicrobial to indirectly select for organisms with medically 
important antimicrobial resistance mechanisms via coselection 
mechanisms, such as coresistance and cross-resistance.
    As antimicrobial resistance is an evolving topic with emerging 
resistance mechanisms being routinely developed and discovered, this 
risk-based approach provides the flexibility needed to address changes 
in future antimicrobial utility and the expanding AMR landscape. 
Classifying these wound dressings and liquid wound washes will provide 
clarity and transparency regarding the regulatory requirements (e.g., 
general controls, special controls, or premarket approval) necessary to 
provide a reasonable assurance of safety and effectiveness. As 
antimicrobial resistance remains a priority for FDA, such an effort 
will further enhance our ongoing activities related to slowing the 
development of AMR to help ensure safe and effective use of 
antimicrobials in wound dressings and liquid wound washes intended for 
human use.

C. FDA's Current Regulatory Framework

    The FD&C Act (21 U.S.C. 301 et seq.), as amended by the Medical 
Device Amendments of 1976 (1976 amendments) (Pub. L. 94-295), 
established a comprehensive system for the regulation of medical 
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C. 
360c) established three classes of devices, reflecting the regulatory 
controls needed to provide reasonable assurance of their safety and 
effectiveness: class I (general controls), class II (general controls 
and special controls), and class III (premarket approval and general 
controls).
    Section 513(a)(1) of the FD&C Act defines the three classes of 
devices. Class I devices are those devices for which the general 
controls of the FD&C Act (controls authorized by or under sections 501, 
502, 510, 516, 518, 519, or 520 of the FD&C Act (21 U.S.C. 351, 352, 
360, 360f, 360h, 360i, or 360j) or any combination of such sections) 
are sufficient to provide reasonable assurance of safety and 
effectiveness, or those devices for which insufficient information 
exists to determine that general controls are sufficient to provide 
reasonable assurance of safety and effectiveness or to establish 
special controls to provide such assurance, but because the devices are 
not purported or represented to be for a use in supporting or 
sustaining human life or for a use which is of substantial importance 
in preventing impairment of human health, and do not present a 
potential unreasonable risk of illness or injury, are to be regulated 
by general controls (section 513(a)(1)(A) of the FD&C Act).
    Class II devices are those devices for which general controls by 
themselves are insufficient to provide reasonable assurance of safety 
and effectiveness, but for which there is sufficient information to 
establish special controls to provide such assurance, including the 
promulgation of performance standards, postmarket surveillance, patient 
registries, development and dissemination of guidelines (including 
guidelines for the submission of clinical data in premarket 
notification submissions in accordance with section 510(k)), 
recommendations, and other appropriate actions as the Secretary deems 
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C 
Act).
    Class III devices are those devices for which insufficient 
information exists to determine that general controls (controls 
authorized by or under sections 501, 502, 510, 516, 518, 519, or 520 of 
the FD&C Act or any combination of such sections) and special controls 
would provide a reasonable assurance of safety and effectiveness, and 
are purported or represented for a use in supporting or sustaining 
human life or for a use which is of substantial importance in 
preventing impairment of human health, or present a potential 
unreasonable risk of illness or injury (section 513(a)(1)(C) of the 
FD&C Act).
    Under section 513(d) of the FD&C Act, FDA refers to devices that 
were in commercial distribution before the 1976 amendments as 
``preamendments devices.'' FDA classifies these devices after the 
Agency: (1) receives a recommendation from a device classification 
panel (an FDA advisory committee); (2) publishes the panel's 
recommendation for comment, along with a proposed regulation 
classifying the device; and (3) publishes a final regulation 
classifying the device (section 513(d)(1) of the FD&C Act). FDA has 
classified most preamendments devices under these procedures.
    A person may market a preamendments device that has been classified 
into class III through premarket notification procedures without 
submission of a PMA until FDA issues a final regulation order under 
section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) requiring premarket 
approval. FDA is also proposing, by proposed order published elsewhere 
in this issue of the Federal Register, to require the filing of PMAs 
for such devices.
    After the enactment of the 1976 amendments, FDA undertook to 
identify and classify all preamendments devices in accordance with 
section 513(d) of the FD&C Act. As part of this effort, FDA has 
completed the classification process to classify four types of wound 
dressings, as class I medical devices: (1) nonresorbable gauze/sponge 
for external use at Sec.  878.4014; (2) hydrophilic wound dressing at 
Sec.  878.4018; (3) occlusive wound dressing at Sec.  878.4020; and (4) 
hydrogel wound dressing and burn dressing at Sec.  878.4022. However, 
wound dressings that contain antimicrobials and/or other chemicals were 
not included in these prior actions and have not been separately 
classified to date.

D. History of This Rulemaking

    As described previously, certain solid wound dressings; wound 
dressings formulated as a gel, cream, or ointment; and liquid wound 
washes containing antimicrobials and/or other chemicals are 
unclassified, preamendments devices. These devices have been subject to 
premarket review through a 510(k) submission and have been cleared for 
marketing if FDA considers the device to be substantially equivalent to 
a legally marketed predicate in accordance with section 513(i) of the 
FD&C Act. Currently, there are more than 500 legally marketed 
unclassified, preamendments wound dressings and liquid wound washes 
containing antimicrobials and/or other chemicals

[[Page 83782]]

which have been cleared through the 510(k) pathway that would be 
subject to this proposed classification regulation.
    Consistent with the FD&C Act, FDA convened the General and Plastic 
Surgery Devices Panel of the Medical Devices Advisory Committee and 
held multiple meetings regarding the classification of wound dressings 
on: (1) November 27, 1998 (Ref. 1); (2) August 25 and 26, 2005 (Ref. 
2); and (3) September 20 and 21, 2016 (Ref. 3). From these meetings, 
and FDA's research and findings, the Agency understands that wound 
dressings and liquid wound washes containing medically important 
antimicrobials pose more AMR risk than other wound dressings and liquid 
wound washes. Elsewhere in this issue of the Federal Register, FDA is 
proposing to classify unclassified, preamendments wound dressings and 
liquid wound washes containing medically important antimicrobials into 
class III. FDA is proposing this classification as FDA believes that 
insufficient information exists to determine that general controls and 
special controls would provide reasonable assurance of the safety and 
effectiveness of these devices and these devices present a potential 
unreasonable risk of illness or injury. The proposed rule would also 
establish the identification, classification, and regulatory controls 
for certain solid wound dressings; wound dressings formulated as a gel, 
cream, or ointment; and liquid wound washes that contain antimicrobials 
and/or other chemicals.
1. 1998 General and Plastic Surgery Devices Panel
    On November 27, 1998, FDA convened the General and Plastic Surgery 
Devices Panel (the 1998 Panel) to discuss the classification of five 
wound dressing categories and the reclassification of topical oxygen 
chambers for extremities (Ref. 1). At the meeting, FDA presented the 
following five types of unclassified, preamendments wound dressings for 
the 1998 Panel's classification recommendations: (1) nonresorbable 
gauze/sponges for external use; (2) hydrophilic wound dressings; (3) 
occlusive wound dressings, (4) hydrogel wound dressings; and (5) 
porcine wound dressings. FDA requested the 1998 Panel consider the 
proposed classifications for each of these wound dressings, including 
the product description and intended uses that should be included in 
the classification regulation for each dressing. FDA also requested the 
1998 Panel discuss the risks to health for each dressing. FDA asked the 
1998 Panel, as part of their deliberations, to consider the potential 
risk of viral transmission posed by porcine wound dressings.
    The 1998 Panel unanimously concurred with a recommendation that all 
five identified wound dressings be classified in class I. The 1998 
Panel also recommended that four of the five dressings: (1) 
nonresorbable gauze/sponges for external use; (2) hydrophilic wound 
dressings; (3) occlusive wound dressings; and (4) hydrogel wound 
dressings, be classified as exempt from premarket notification 
requirements. Subsequently, FDA classified these four dressing types 
under Sec. Sec.  878.4014, 878.4018, 878.4020, and 878.4022, 
respectively (Ref. 4). Therefore, since these four dressings were 
previously classified, they are outside the scope of this proposed rule 
and will not be discussed further in this proposed rule. The fifth 
dressing type, porcine wound dressings, remained unclassified following 
the 1998 Panel meeting.
    Although the 1998 Panel recommended that porcine wound dressings 
should be class I, the 1998 Panel believed that porcine wound dressings 
should not be exempt from premarket notification requirements due to 
concerns of potential viral contaminants and infectious diseases. Since 
FDA believes the risks of porcine wound dressings identified at the 
1998 Panel meeting are also relevant to the wound dressings composed of 
animal-derived materials described in this proposed rule, a brief 
summary of the 1998 Panel discussion on porcine wound dressings is 
provided here. After considering the information provided by FDA, the 
open discussions during the 1998 Panel meeting, and the 1998 Panel 
members' experiences with these wound dressings at that time, the 1998 
Panel provided reasons in support of its recommendation for classifying 
porcine wound dressings used to provide or support a moist wound 
environment, to cover a wound, to absorb exudate, and/or to minimize 
fluid loss into class I, not exempt from premarket notification 
requirements.
2. 2005 General and Plastic Surgery Devices Panel
    On August 25 and 26, 2005, the General and Plastic Surgery Devices 
Panel (the 2005 Panel) met to provide advice and recommendations on the 
classification of five unclassified preamendments medical devices: (1) 
bone wax; (2) medical maggots; (3) medicinal leeches; (4) tissues 
expanders; and (5) wound dressings containing antimicrobials and/or 
other chemicals; however, for the purposes of this proposed rule, only 
the 2005 Panel's recommendations regarding wound dressings containing 
antimicrobials and/or other chemicals will be discussed (Ref. 2). At 
the 2005 Panel meeting, FDA proposed to describe the intended uses for 
these wound dressings containing antimicrobials and/or other chemicals, 
whether sterile or nonsterile, as being used to cover a wound, to 
absorb exudate, to provide or support a moist environment within the 
dressing, and to control bleeding or fluid loss. These wound dressings 
consist of nonabsorbable materials and contain added antimicrobials 
and/or other chemicals.
    The 2005 Panel unanimously concurred to recommend that FDA classify 
wound dressings containing antimicrobials and/or other chemicals as 
class II medical devices requiring a 510(k) submission, subject to 
special controls. Some of the major risks identified by the 2005 Panel 
included the possibility that the antimicrobials and/or other chemicals 
could contribute to antimicrobial resistance, could sensitize the skin, 
interfere with wound healing, or result in selective colonization. But 
the 2005 Panel agreed with FDA that there is sufficient information to 
establish special controls that, together with general controls, would 
mitigate the risks to health and provide a reasonable assurance of 
safety and effectiveness for these products.
3. 2016 General and Plastic Surgery Devices Panel
    The most recent Panel, held on September 20 and 21, 2016 (the 2016 
Panel), met for the purposes of obtaining recommendations about the 
classification of products, including: (1) solid wound dressings; (2) 
wound dressings formulated as a gel, cream, or ointment; and (3) liquid 
wound washes. FDA held the 2016 Panel to obtain input on the benefits 
and risks of wound dressings and liquid wound washes that contain 
antimicrobials and/or other chemicals, as well as on the clinical 
relevance of certain indications. The 2016 Panel was asked to recommend 
to FDA whether such wound dressings and liquid wound washes that 
contain antimicrobials and/or other chemicals should be classified into 
class III (subject to PMA and general controls), class II (subject to 
general and special controls), or class I (subject only to general 
controls). The 2016 Panel was also asked to discuss the types of 
evidence (including clinical evidence) that would be helpful to support 
certain indications, as well as the appropriate controls necessary to 
mitigate the risks to health and assure the safety and

[[Page 83783]]

effectiveness of these types of wound dressings and liquid wound 
washes.
    For each type of wound dressing and liquid wound wash, FDA 
presented the proposed risks to health and proposed mitigation 
measures. FDA identified risks to health applicable to wound dressings 
and liquid wound washes, including adverse tissue reaction, delayed 
wound healing, incompatibilities with other therapies, increased risk 
of AMR, infection, microbial growth, and product degradation. Further, 
FDA identified that additional risks to health applicable to solid 
wound dressings included loss of barrier function and retention of 
dressing material in the wound. FDA also identified that an additional 
risk applicable to liquid wound washes was the inability to remove 
wound debris. Following the 2016 Panel meeting, an additional risk to 
health was identified based on emerging reports in the literature 
(Refs. 31-37) regarding the understood role that our skin microbiota 
plays in the wound healing cascade. As such, antimicrobials that leach 
from wound dressings may inadvertently negatively impact the patient's 
skin microbiota in the periwound area resulting in impaired wound 
healing.
    FDA presented information on the proposed mitigation measures for 
the risks to health of these wound dressings and liquid wound washes, 
which included biocompatibility, in vivo evaluation, clinical 
evaluation of dressings for specific intended uses and indications for 
use, labeling, evaluation and identification of any probable risk and 
mechanisms for AMR, sterilization and shelf-life validation, 
preservative effectiveness testing, and antimicrobial effectiveness 
testing. In addition to these identified mitigation measures, FDA 
proposed that the risk of loss of barrier function associated with 
solid wound dressings could be mitigated through microbial barrier 
effectiveness testing and water loss/moisture barrier effectiveness 
testing. Similarly, FDA proposed that the risk of inability to remove 
wound debris and foreign materials associated with liquid wound washes 
could be mitigated through appropriate bench performance testing. 
Regarding the understood risk that antimicrobials may inadvertently 
negatively impact the skin microbiota in the periwound area and impair 
wound healing, FDA proposes that this risk may be mitigated through 
antimicrobial characterization, performance testing, and labeling.
    Regarding the benefit and risk assessments, the 2016 Panel noted 
that it is important to consider the heterogeneity in wound types when 
evaluating whether labeling claims represent clinically meaningful 
benefit to patients. For example, a labeling claim specifying use for a 
specific amount of time may be highly beneficial for dressings intended 
to be placed over a central venous catheter, but may not be as 
beneficial for burn wounds. The 2016 Panel also noted that when 
assessing the benefit-risk profile of a product, higher risk may be 
tolerated when known benefit is high, whereas lower risk should be 
tolerated when known benefit is low or not established.
    Regarding factors to consider when more than one antimicrobial is 
included in a single product, the 2016 Panel stated that it would be 
important to evaluate whether use of multiple antimicrobials in a 
single product would produce antagonistic, synergistic, or additive 
effects with respect to reducing bioburden and/or promoting AMR. The 
2016 Panel noted that it is currently not well understood how the 
inclusion of more than one antimicrobial would impact the likelihood of 
developing AMR. When certain antimicrobials are used together, there is 
surveillance data that shows that the risk of selecting for resistance 
is higher. However, the 2016 Panel noted that sufficient surveillance 
data does not exist for many other groupings of antimicrobials.
    For solid wound dressings, a majority of the 2016 Panel members 
recommended that these products be classified into class II, subject to 
special controls, with the exception of certain solid wound dressings 
containing antimicrobials, such as antibiotics (with similar 
consideration to antimicrobial agents that may select for resistance in 
indirect ways). For these exceptions, several members of the 2016 Panel 
recommended that these wound dressings be classified into class III, 
with one Panel member noting that ``antibiotics should be held to an 
extremely high set of standards to prove value because of the risk of 
[antimicrobial] resistance]''. Further, the 2016 Panel meeting included 
discussion to note that special controls, such as testing in an animal 
model, could not be used to evaluate and/or mitigate the risk of AMR, 
supporting the assertion of several Panel members that solid wound 
dressings containing antibiotics should be classified as class III 
devices. As such, some of the 2016 Panel members recommended that the 
AMR risk posed by certain antimicrobials, such as antibiotics, could be 
mitigated through the increased controls of the PMA regulatory pathway 
that would be applied to these wound dressings as class III devices.
    Several of the 2016 Panel members stated that additional risks 
associated with solid wound dressings containing antimicrobials may 
include leaching and systemic absorption of the antimicrobials, delayed 
wound healing, retention of dressing material in the wound, and loss of 
barrier function. Regarding mitigation of risks, some 2016 Panel 
members stated that bench testing could be a potential mitigation 
measure for the risk of retention of dressing material in the wound. 
One Panel member added that labeling would be an additional mitigation 
measure for loss of barrier function since barrier function would be 
dependent on proper application of the wound dressing. The risk of 
leaching and systemic adsorption of antimicrobials and/or other 
chemicals is also covered in adverse tissue reaction and toxicity.
    For wound dressings formulated as a gel, cream, or ointment, a 
majority of the 2016 Panel members recommended that these products be 
classified into class II, subject to special controls, with the 
exception of certain wound dressings formulated as a gel, cream, or 
ointment containing antimicrobials, such as antibiotics (with similar 
consideration to antimicrobial agents that may select for resistance in 
indirect ways), for which some members of the 2016 Panel recommended 
class III. Several of the 2016 Panel members referenced the prior 
discussion on solid wound dressings, wherein they recommended that 
classification should be stratified by the risk of the ingredients 
within the dressing. The reasons certain wound dressings formulated as 
a gel, cream, or ointment should be classified as class III devices, 
based on the inclusion of certain antimicrobials, such as antibiotics, 
aligned with the rationale discussed during the deliberations on solid 
wound dressings. Also, some 2016 Panel members stated that cumulative 
residual material in the wound could present an additional potential 
risk that could be mitigated by specific labeling requirements. The 
risks of systemic absorption and topical toxicity were also concerning 
to the 2016 Panel. Some 2016 Panel members questioned whether 
antimicrobials should be included in a gel, cream, or ointment at all 
when there may be physical or non-antimicrobial means to reduce 
bioburden in the product.
    For liquid wound washes, a majority of the 2016 Panel recommended 
that these products be classified into class I or class II, subject to 
special controls, depending on the toxicity of the product, with the 
exception of certain liquid wound washes containing antimicrobials, 
such as antibiotics (with

[[Page 83784]]

similar consideration to antimicrobial agents that may select for 
resistance in indirect ways), for which some members of the 2016 Panel 
recommended class III. To support this opinion on classifying liquid 
wound washes containing antimicrobials, such as antibiotics, as class 
III devices, several of the 2016 Panel members referenced the prior 
discussion regarding solid wound dressings, where it was noted that 
special controls could not mitigate the risks posed by these products 
and that classification of these products should be stratified based on 
risk of AMR. Some of the 2016 Panel members felt that the identified 
risk of ``inability to remove wound debris and foreign materials'' 
would be better refined as ``inadequate or possible incomplete removal 
of wound debris and foreign materials.'' The 2016 Panel discussed the 
clinical value of debridement and irrigation and questioned the value 
of added agents. There was agreement that agents in the liquid wound 
wash would affect the wound directly, and there was skepticism 
regarding whether these products should contain antimicrobials at all.

IV. Legal Authority

    The Agency is proposing this classification under the authority of 
section 301 of the FD&C Act (21 U.S.C. 301). Specifically, the relevant 
authority related to the proposed classification includes sections 
513(a) through (d) of the FD&C Act regarding device classes, 
classification, and panels; section 515 of the FD&C Act regarding PMAs; 
and section 701(a) of the FD&C Act (21 U.S.C. 371(a)).

V. Description of the Proposed Rule

A. Scope/Applicability

    We are proposing to amend subpart E of 21 CFR part 878 by adding 
Sec.  878.4016 to classify solid wound dressings containing 
antimicrobials and/or other chemicals used to cover and protect a 
wound, to absorb exudate, and to maintain appropriate moisture balance 
within the wound; Sec.  878.4017 to classify wound dressings formulated 
as a gel, cream, or ointment containing antimicrobials and/or other 
chemicals used to maintain appropriate moisture balance within the 
wound; and Sec.  878.4019 to classify liquid wound washes used to 
mechanically irrigate and physically remove debris from external wounds 
and to moisten solid wound dressings in accordance with section 513(d) 
of the FD&C Act. Please note that wound dressings and liquid wound 
washes generally achieve the maintenance of a moist wound environment 
through nonchemical action (e.g., by acting as a barrier).
    Wound dressings and liquid wound washes that achieve the 
maintenance of a moist wound environment through chemical action would 
be outside the scope of this proposed rule and may be drugs or 
combination products. For information on the classification of products 
as drugs, devices or biological products, see the guidance 
``Classification of Products as Drugs and Devices and Additional 
Product Classification Issues'' (Ref. 38). Examples of antimicrobials 
and categories and examples of other chemicals are identified in tables 
2 and 3, respectively. This proposed classification rule applies to 
certain wound dressings and liquid wound washes currently regulated 
under the product codes FRO, GER, MGP, MGQ, and EFQ. The proposed rule 
only applies to wound dressings and liquid wound washes that are for 
use on external cutaneous (skin) wounds.
    The following categories of wound dressings are outside the scope 
of this proposed rule and classification action because they are 
currently regulated either as a distinct category within the product 
code FRO or under a different product code,\19\ as identified:
---------------------------------------------------------------------------

    \19\ More detail about the medical device names and associated 
information for the product codes listed here is available in the 
Product Code Classification Database, available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm.
---------------------------------------------------------------------------

     Wound dressings composed of animal-derived materials 
without the presence of antimicrobials and/or other chemicals, as they 
are currently regulated under product code KGN.
     Wound dressings with or without an added antimicrobial or 
biologic (e.g., thrombin) that is used to provide hemostasis through 
accelerated blood clotting when combined with manual compression, as 
they were discussed in October 2022 at a Classification 
Panel.20 21
---------------------------------------------------------------------------

    \20\ 87 FR 60691, October 6, 2022. Available at https://www.govinfo.gov/content/pkg/FR-2022-10-06/pdf/2022-21746.pdf. FDA 
will add a link to the meeting materials once they are publicly 
available.
    \21\ These dressings are currently regulated under product code 
FRO, but FDA's intent will be to assign a new product code for these 
wound dressings as they are out of the scope of this proposed rule 
and proposed classification action.
---------------------------------------------------------------------------

     Absorbable synthetic wound dressings without 
antimicrobials that are intended to degrade and be resorbed into the 
wound.\22\
---------------------------------------------------------------------------

    \22\ Id.
---------------------------------------------------------------------------

     Catheter securement dressings containing antimicrobials 
that are intended for reduction or prevention of infection (e.g., 
central line-associated bloodstream infection).23 24
---------------------------------------------------------------------------

    \23\ The majority of the catheter securement dressings with 
antimicrobials are in scope for this proposed rule and proposed 
classification action. Catheter securement dressings containing 
antimicrobials that are intended for reduction or prevention of 
infection are outside the scope of this proposed rule.
    \24\ These dressings are currently regulated under product code 
FRO, but FDA's intent will be to assign a new product code for these 
wound dressings, as they are out of scope of this proposed rule and 
proposed classification action.
---------------------------------------------------------------------------

     Dressings with topical analgesics, such as lidocaine or 
benzocaine.25
---------------------------------------------------------------------------

    \25\ Id.
---------------------------------------------------------------------------

     Dressings with hydrocortisone.26
---------------------------------------------------------------------------

    \26\ Id.
---------------------------------------------------------------------------

     Wound dressings used on mucosa, such as for oral uses or 
use in the gastrointestinal tract. The following categories of wound 
dressings are outside the scope of this proposed rule and 
classification action because FDA has previously classified them:
     Nonresorbable gauze/sponge for external use at Sec.  
878.4014 (Product Codes: MAC, OVR, LZM, NAB, OHO, PKD, PXY, PYJ, PYK, 
PYL);
     Hydrophilic wound dressing at Sec.  878.4018 (Product 
Codes: KOZ, MGO, NAC);
     Occlusive wound dressing at Sec.  878.4020 (Product Code: 
NAD);
     Hydrogel wound dressing and burn dressing at Sec.  
878.4022 (Product Codes: NAE, OJJ, PXQ);
     Wound dressing with poly (diallyl dimethyl ammonium 
chloride) (pDADMAC) additive at Sec.  878.4015 (Product Code: NYS).

(Refs. 39-40)

B. Device Description

1. Solid Wound Dressings Containing Antimicrobials and/or Other 
Chemicals
    Solid wound dressings containing antimicrobials and/or other 
chemicals are used to cover and protect a wound, to absorb exudate, and 
to maintain appropriate moisture balance within the wound (see intended 
uses in section V.B). The antimicrobials (see table 2) contained in 
solid wound dressings are used as a protectant to prevent or reduce 
contamination or deterioration of the dressing while in contact with 
the wound. A solid wound dressing may contain one or more of the 
antimicrobials (see table 2) and/or other chemicals (see table 3). Such 
a wound dressing may also contain animal-derived materials (e.g., 
collagen, gelatin, decellularized extracellular matrix).
    The dressing materials are resorbable or nonresorbable, synthetic 
or naturally derived materials (including animal-derived materials), 
which are provided

[[Page 83785]]

sterile in a form able to hold structural integrity permanently or 
temporarily. Solid wound dressings containing antimicrobials and/or 
other chemicals may be in the form of a woven or nonwoven fabric pad, 
foam, or as a cross-linked hydrogel that has sufficient structural 
integrity to hold a physical form, such as a scaffold or matrix. Some 
wound dressings are multilayered, with each layer made of a different 
solid form, such as a four-layered dressing with a woven layer, foam 
layer, hydrocolloid layer, and occlusive adhesive backing layer. The 
types of materials used in these wound dressings generally include 
polyester, cellulose, polyurethane, nylon, poly(vinyl alcohol), 
alginate, cross-linked collagen, poly(ethylene glycol), and 
poly(lactic-co-glycolic acid).
2. Wound Dressings Formulated as a Gel, Cream, or Ointment Containing 
Antimicrobials and/or Other Chemicals
    A wound dressing formulated as a gel, cream, or ointment containing 
antimicrobials and/or other chemicals is used to maintain appropriate 
moisture balance within the wound (see intended uses in section V.B). 
The antimicrobials contained in such wound dressings are used for 
preservative purposes to maintain shelf life for a nonsterile wound 
dressing or a multiple-use wound dressing for single patient use only 
(see table 2). A wound dressing formulated as a gel, cream, or ointment 
may contain one or more of the antimicrobials (see table 2) and/or 
other chemicals (see table 3). Such a wound dressing may also contain 
animal-derived materials.
    The wound dressing materials are synthetic or naturally derived 
materials (including animal-derived materials), which are provided in 
an amorphous form. Wound dressings formulated as a gel, cream, or 
ointment containing antimicrobials and/or other chemicals are amorphous 
and can have high water content with thickening agents or consist of an 
oil-water emulsion. These products are generally packaged in tubes or 
containers that can be for single use only or labeled for multiple use 
for single patient use only after the package has been opened. While 
some wound dressings are terminally sterilized and labeled for single 
use, many other wound dressings cannot be terminally sterilized given 
the sensitivity of the materials to sterilization methods, or they may 
require a preservative for multiple-use wound dressings for single 
patient use only.
3. Liquid Wound Washes
    A liquid wound wash is a water-based solution used to mechanically 
irrigate and physically remove debris from external wounds. It is also 
used to moisten solid wound dressings to maintain appropriate moisture 
balance within the dressing (see intended use(s) in section V.B). The 
antimicrobials contained in such liquid wound washes are used for 
preservative purposes to maintain shelf life for a nonsterile liquid 
wound wash or a multiple-use liquid wound wash for single patient use 
only (see table 2). Some liquid wound washes are terminally sterilized 
and labeled for single use, or they may require a preservative for 
multiple-use liquid wound washes for single patient use only. Liquid 
wound washes may contain one or more of the antimicrobials (see table 
2) and/or other chemicals (see table 3).
    Liquid wound washes are generally water- or saline-based liquid 
solutions. They are typically packaged in bottles with plain caps or 
pump sprays and may or may not be terminally sterilized. Such liquid 
wound washes may also contain animal-derived materials.
4. Proposed Intended Use(s)
    Based on the collective recommendations from the 2005 and 2016 
Panels, FDA's experience with these wound dressings and liquid wound 
washes, and other available information, FDA proposes the following 
intended uses for the three wound dressing and liquid wound wash types 
discussed in this proposed rule. Additionally, since the utilization of 
these wound dressings and liquid wound washes is not to treat an 
infection, FDA is proposing that the intended uses for these wound 
dressings and liquid wound washes remain the same whether the product 
is used for an infected or noninfected wound because the role of the 
antimicrobial is limited to acting within the dressing and not on the 
wound itself. The proposed uses are the following:
     Solid Wound Dressings Containing Antimicrobials and/or 
Other Chemicals: A solid wound dressing containing antimicrobials and/
or other chemicals is used to cover and protect a wound, to absorb 
exudate, and to maintain appropriate moisture balance within the wound.
     Wound Dressings formulated as a Gel, Cream, or Ointment 
Containing Antimicrobials and/or Other Chemicals: A wound dressing 
formulated as a gel, cream, or ointment containing antimicrobials and/
or other chemicals is used to maintain appropriate moisture balance 
within the wound.
     Liquid Wound Washes: A liquid wound wash is a water-based 
solution used to mechanically irrigate and physically remove debris 
from external wounds. It is also used to moisten solid wound dressings 
to maintain appropriate moisture balance within the dressing.
    Within those intended uses, antimicrobials may support the intended 
use through the following means:
     Antimicrobial preservative: An antimicrobial preservative 
is used in wound dressings formulated as a gel, cream, or ointment or 
liquid wound washes to maintain low bioburden while in its packaging 
during storage to improve its shelf life. An antimicrobial preservative 
use is not appropriate for a sterile, single-use product. Further, 
preservative effectiveness claims are within the scope of this proposed 
rule for the proposed classifications only when used for a specified 
period of use for multiple-use wound dressings and liquid wound washes 
for single patient only use.
     Antimicrobial protectant: An antimicrobial protectant, 
when added to a sterile, single-use solid wound dressing, is intended 
to support the use of the wound dressing by reducing degradation or 
biofouling of the dressing while in use. Antimicrobial protectant 
claims are within the scope of this proposed rule for the proposed 
classifications only when used for reducing microbial growth within the 
solid wound dressing for a specified maximum period of clinical use.
    Prior to this proposed rulemaking, wound dressings and liquid wound 
washes containing antimicrobials intended for wound management were 
generally identified as combination products.\27\ This was because the 
term ``wound management'' could be interpreted broadly, encompassing 
uses not only including to cover and protect a wound, to absorb 
exudate, and to maintain appropriate moisture balance, but also uses 
such as treatment of wounds/wound infection. As discussed in more 
detail below, for a product to be within the scope of this proposed 
rulemaking and benefit from the proposed classification action, FDA is 
proposing that the term ``wound management'' not be included in the 
product labeling and the product labeling be clarified to reflect the

[[Page 83786]]

explicit uses described above (e.g., ``to protect and cover a wound'').
---------------------------------------------------------------------------

    \27\ See definition of combination product in 21 CFR 3.2(e).
---------------------------------------------------------------------------

    FDA has considered the intended use of these products in this 
category limited to the uses expressly discussed above (including to 
cover and protect a wound, to absorb exudate, to maintain appropriate 
moisture balance, to mechanically irrigate). However, with the 
inclusion of ``wound management'' and based on feedback during the 2016 
Panel (Ref. 3), these limited intended uses were not clear to all users 
and, thus, created a broader objective intent. Within the scope of this 
proposed rule, FDA is making manufacturers aware that, for their 
products to be within the scope of this proposed rulemaking and benefit 
from the proposed classification action, manufacturers must clarify 
their labeling to not include ``management'' but instead explicitly 
include the relevant uses described above. Otherwise, the product could 
be subject to a different type of marketing authorization, depending on 
the product claims. In many cases, refinement of the indications will 
require revisions to the labeling.
    FDA believes that, with such clarification of statements in the 
labeling and the indications, wound dressings and liquid wound washes 
in this category, including those with appropriate amounts of 
antimicrobial, should be regulated only as ``devices'' and not as 
combination products. This is because the antimicrobial, when included 
in a product that only covers and protects a wound, absorbs exudate, 
irrigates a wound, and/or maintains appropriate moisture balance would 
not achieve its primary intended purpose through chemical action within 
or on the body of man.\28\
---------------------------------------------------------------------------

    \28\ See section 201(h) of the FD&C Act (21 U.S.C. 321(h))--for 
the definition of device. For guidance on how products are 
classified as devices, please see the guidance ``Classification of 
Products as Drugs and Devices and Additional Product Classification 
Issues'' (https://www.fda.gov/media/80384/download).
---------------------------------------------------------------------------

    Manufacturers who do not intend to update their products' labeling 
to clarify such claims (i.e., update to remove wound management and 
other misleading claims discussed below) would not be in compliance 
with the special controls when the rule is finalized. Hence, these 
manufacturers' products could be subject to submission of their wound 
dressing or liquid wound wash to FDA for review via a different type of 
marketing authorization, depending on the product claims. For example, 
wound dressings containing antimicrobials that make certain wound 
management claims may be considered combination products or drugs and 
regulated as such.
    FDA proposes that the following labeling claims are not appropriate 
for the wound dressings and liquid wound washes proposed for 
classification in this proposed rule as these claims may be unclear or 
misleading or indicate an objective intent outside of the intended uses 
discussed above. While some of these uses may have been previously 
reviewed in submissions for wound dressings and liquid wound washes 
within the scope of this rule, FDA is proposing to clarify, consistent 
with the recommendations of the 2005 and 2016 Panels and FDA's 
experience with these dressings and washes, that such uses are 
inappropriate for the wound dressings and liquid wound washes being 
proposed for classification through this rulemaking. These uses include 
the following:
     Wound Management: While the term has been widely used, it 
is not consistently used and is unclear from a clinical perspective. 
Based on the 2016 Panel discussion, the Panel members agreed that 
specific functions of wound dressings and liquid wound washes had clear 
benefits, including covering and protecting a wound, keeping the 
dressing moist, and washing or irrigating a wound. Although the term 
``wound management'' was presented as a typical part of the indications 
and intended use of wound dressings and liquid wound washes, the 2016 
Panel members acknowledged that there was not a consistent or frequent 
use of the term ``wound management'' in describing how the products are 
used. The 2016 Panel members questioned whether the wound dressings and 
liquid wound washes are intended to treat the wound or to achieve wound 
healing. Therefore, consistent with the 2016 Panel's feedback, this 
proposed rulemaking is clarifying that the term ``wound management'' be 
replaced with the specific functions of the wound dressing and liquid 
wound washes (e.g., cover and protect the wound in the case of solid 
wound dressings).
     Use of the word ``may'' (e.g., ``may reduce the risk of 
infection''): The word ``may'' is ambiguous and could mislead the end 
users when describing a specific use (e.g., ``may reduce the risk of 
infection''); instead, intended uses, indications, and claims should be 
clearly stated and supported by appropriate data. This is supported by 
the fact that the 2016 Panel discussed whether the term ``may reduce 
the risk of infection'' represented a clinically meaningful benefit to 
the patient, and noted that such a claim does not appear to be 
meaningful and is likely confusing to patients.
     Treatment of or cure for wounds: This use is for wound 
healing through active interaction with the wound. Such a use falls 
within the scope of product codes MGR or MDD, which are regulated as a 
postamendments class III device, subject to PMA.
     Deliver antimicrobials to the wound: Such use suggests an 
intent for the treatment or prevention of infection that generally 
would be achieved through chemical action within or on the wound and 
may not fall under CDRH's jurisdiction. For the purposes of this 
classification action, the role of the antimicrobial(s) is limited to 
acting within the wound dressing or liquid wound wash as either a 
preservative or a protectant of the product.
     Antimicrobial preservative claims for a sterile, single-
use product: Use of a preservative in this context is limited only to 
nonsterile, single-use or multiple-use wound dressings for single 
patient use only.\29\
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    \29\ In rare cases, antimicrobials can be included as a process 
control to reduce bioburden during manufacturing, and this should be 
supported with proper justification and discussed with the review 
team. No performance claims should be made regarding the use of 
antimicrobials as manufacturing process controls.
---------------------------------------------------------------------------

    FDA encourages sponsors to consider the following in support of 
their proposed intended use(s) when demonstrating they fall within the 
scope of this proposed rule and classification action.
     Preservative effectiveness claims for wound dressings 
formulated as a gel, cream, or ointment, and liquid wound washes should 
be defined for a specified period of shelf storage, and supported by 
appropriate in vitro testing as outlined in USP <51> ``Antimicrobial 
Effectiveness Testing,'' including following specific recommendations 
concerning test organisms and acceptance criteria.
     Antimicrobial effectiveness claims for solid wound 
dressings should describe the general level of effectiveness (i.e., 
reduced microbial growth within the solid dressing or barrier to 
microbial penetration through a solid dressing over a specified period 
of use) and should be supported by in vitro test results from a broad 
selection of representative clinically relevant microbial species, as 
described in the proposed performance testing special controls 
identified in section V.B. However, due to the genetic diversity within 
the different microbial species, effectiveness claims on product 
labeling should only describe the general level of effectiveness, 
without listing specific

[[Page 83787]]

test organisms, species, or strains (including drug resistant strains 
such as Methicillin-resistant Staphylococcus aureus).
     Antimicrobial effectiveness claims for solid wound 
dressings should clearly distinguish the types of data used to support 
the claim; for example, whether the claim is based on results from in 
vitro testing, in vivo testing, or supporting clinical data. For claims 
that are solely supported by in vitro testing, the submission and 
product labeling should clearly state that the claims are solely based 
on in vitro testing and that clinical studies were not conducted or 
that the clinical benefit has not been evaluated.
     Antimicrobial and preservative effectiveness claims for 
all wound dressings containing antimicrobials should not state or imply 
that these products have an antimicrobial impact on organisms in the 
wound environment since claims regarding effectiveness against wound 
microorganisms and biofilms would be outside the scope of this proposed 
rule.

C. Risks to Health and Public Health Benefits

    In evaluating the risks to health associated with the use of wound 
dressings and liquid wound washes, FDA considered information from the 
1998 Panel, the 2005 Panel, and the 2016 Panel regarding the 
classification of wound dressings and liquid wound washes; the adverse 
event reports for these wound dressings and liquid wound washes in 
FDA's Manufacturer and User Facility Device Experience database 
examined through July 2022; and the published scientific literature, 
which is discussed in FDA's executive summary for the 2016 Panel 
meeting (Ref. 3).
    FDA also considered scientific literature published since the 2016 
Panel meeting. A contemporary literature search was conducted in 
September 2022 and identified eight articles (Refs. 41-48) published 
since June 2016 that are relevant to the safety and effectiveness of 
wound dressings and liquid wound washes containing antimicrobials. In 
the review of these references, the information from the contemporary 
literature analysis is consistent with the findings of the prior 
literature analysis presented at the 2016 Panel meeting.
    FDA also reviewed recalls reported under product code FRO from 2003 
to July 2022.\30\ There were no recalls for solid wound dressings; 
wound dressings formulated as a gel, cream, or ointment; or liquid 
wound washes containing medically important antimicrobials acting as 
either protectants or preservatives during this same timeframe. Out of 
the 29 recalls identified for wound dressings and liquid wound washes 
containing medium or low level of AMR concern and/or other chemicals, 
there was 1 class I recall, 23 class II recalls, and 5 class III 
recalls. The reason for the one class I recall was potential microbial 
contamination of the product. Reasons for class II and class III 
recalls include erroneous device labeling, devices not meeting 
stability specifications, and potential sterility breach of the 
product. Based on this information, FDA believes the risks to health 
associated with the use of these wound dressings and liquid wound 
washes are those discussed below.
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    \30\ Only the product code FRO was queried for the recall 
analysis, as the majority of the products in scope for this proposed 
rule fall within FRO. The types of recalls reported within FRO are 
expected to be representative of all products in scope for this 
proposed rule.
---------------------------------------------------------------------------

    Based on this information, FDA has identified the following risks 
to health to the different categories of wound dressings and liquid 
wound washes which are within the scope of this proposed rule and 
classification action:
     Solid Wound Dressings: adverse tissue reaction, 
immunological reaction, transmission of pathogens and parasites, 
toxicity, delayed wound healing, incompatibilities with other 
therapies, contribution to the spread of AMR, infection, microbial 
growth within the product, product degradation during stated shelf 
storage, loss of barrier function, retention of dressing material in 
wound, and negatively impacting the skin microbiota in the periwound 
area resulting in impaired wound healing.
     Wound Dressings Formulated as a Gel, Cream, or Ointment: 
adverse tissue reaction, immunological reaction, transmission of 
pathogens and parasites, toxicity, delayed wound healing, 
incompatibilities with other therapies, contribution to the spread of 
AMR, infection, microbial growth within the product, product 
degradation during stated shelf storage, and negatively impacting the 
skin microbiota in the periwound area resulting in impaired wound 
healing.
     Liquid Wound Washes: adverse tissue reaction, 
immunological reaction, transmission of pathogens and parasites, 
toxicity, delayed wound healing, incompatibilities with other 
therapies, contribution to the spread of AMR, infection, microbial 
growth within the product, product degradation during stated shelf 
storage, inability to remove wound debris and foreign materials, and 
negatively impacting the skin microbiota in the periwound area 
resulting in impaired wound healing.
    Below is a brief description of each of the identified risks to 
health:
     Adverse tissue reaction: Erythema, irritation, 
inflammation of the wound or host tissue, immune response, and 
hemolysis can occur as a result of an unwanted tissue response 
associated with the materials or leachables/extractables in wound 
dressings and liquid wound washes.
     Immunological reaction: This can result from a device 
derived from a new animal source or protein denaturation/modification 
due to the manufacturing conditions.
     Transmission of pathogens and parasites (e.g., bacteria, 
mycoplasma, fungi, viruses, and other transmissible spongiform 
encephalopathy agents): This can result from contaminated animal 
sources, feed, inadequate processing, and viral inactivation of the 
animal-derived materials.
     Toxicity: Local and/or systemic toxicity, tissue necrosis, 
reduced tissue viability, and genotoxicity can occur due to toxic 
antimicrobials or other chemicals in the wound dressings or liquid 
wound washes, which can result in adverse tissue effects, leading to 
toxicity. This also includes allergic reaction and sensitization, as 
individuals with known sensitivity to the materials in the wound 
dressings and liquid wound washes may experience allergic reactions, 
which may be severe depending on the degree of sensitivity.
     Delayed wound healing: Cytotoxicity resulting in dead or 
necrotic tissue can delay healing.
     Incompatibilities with other therapies: An undesirable 
(e.g., antagonistic) reaction could occur between the materials 
contained in/on the wound dressings or liquid wound washes and other 
therapies applied to the wound.
     Contribution to the spread of AMR: Use of antimicrobials 
in wound dressings and liquid wound washes can inadvertently select for 
and cultivate antimicrobial resistant organisms in patients and further 
limit a clinician's therapeutic options to treat infections.
     Infection: Unsafe methods of manufacturing processes, such 
as inadequate aseptic processing, inadequate packaging and/or product 
storage can result in contaminated product that may be a source of 
infection. This risk includes bacterial and fungal infections and 
superinfections which may result from the use of an antimicrobial-
containing

[[Page 83788]]

wound dressing or liquid wound wash that introduces contaminating 
microorganisms to the wound or disrupts the natural balance of skin 
flora around the wound.
     Microbial growth within the product: This can occur from 
inadequate sterilization, preservative effectiveness failure, unsafe 
methods of manufacturing processes, inadequate packaging and/or product 
storage. This can lead to a change in product composition or 
characteristics (e.g., loss of tensile strength, change in pH) and may 
also result in infection or adverse tissue reaction.
     Product degradation during stated shelf storage: 
Inadequate packaging and/or inappropriate storage of wound dressings or 
liquid wound washes can result in product degradation during storage. 
Product degradation can also change the composition or characteristics 
of the product over time and lead to patient harm.
     Retention of dressing material in wound: This risk is 
generally applicable to solid wound dressings, which can occur due to a 
loss in solid dressing integrity or unintended degradation of solid 
wound dressings. It may also occur due to a healthcare provider 
inadvertently leaving material in the wound. This can lead to adverse 
tissue reaction, delay in wound healing, or infection.
     Inability to remove wound debris and foreign materials: 
Ineffective washing of the wound can occur. Debris and foreign material 
remaining in the wound can delay healing or lead to infection. This 
risk is applicable to the liquid wound washes containing antimicrobials 
and/or other chemicals.
     Loss of barrier function: This risk is applicable to solid 
wound dressings indicated as barriers to microbial penetration through 
the wound dressing (either via mechanical or antimicrobial properties). 
Loss of this barrier function can introduce microbial contamination 
from the environment into the wound and can lead to delay in wound 
healing or infection.
     Impact to skin microbiota in the periwound area: This risk 
is applicable to each category of antimicrobial-containing wound 
dressings. Inadvertent leaching of antimicrobials away from the 
dressing may negatively impact the skin microbiota in the periwound 
area by reducing the presence of beneficial commensal microorganisms 
that play a role in the wound healing cascade, resulting in impaired 
wound healing.
    The purported benefits associated with the use of wound dressings 
and liquid wound washes that are proposed to be classified into either 
class III or II are discussed below.
    In evaluating the benefits associated with the use of wound 
dressings and liquid wound washes containing antimicrobials and/or 
other chemicals, FDA considered information from the 1998 Panel, the 
2005 Panel, and the 2016 Panel regarding the classification of wound 
dressings and liquid wound washes and the published scientific 
literature, including clinical guidelines for wound care, which is 
discussed in FDA's executive summary for the 2016 Panel meeting (Ref. 
3). Based on this information, there appears to be a lack of clinical 
data to demonstrate a clear clinical benefit (e.g., improved clinical 
outcomes from the use of antimicrobial dressings over non-antimicrobial 
dressings for the prevention or treatment of local wound infections or 
to improve wound healing) regarding the use of wound dressings and 
liquid wound washes containing antimicrobials and/or other chemicals. 
It is generally understood from the literature review and discussion 
with the 2016 Panel members that the collection of such clinical data 
has been challenging, as a result of many factors (e.g., difficulties 
grouping patients with different wound types, lack of controls, unclear 
endpoints, other treatments including use of systemic antibacterial 
drugs, exclusion criteria, and identifying a sufficient number of 
patients to power these studies). Despite the lack of clear clinical 
data, several benefits to wound dressings and liquid wound washes 
containing antimicrobials and/or other chemicals have been identified, 
including the following:
     Maintaining a moist wound healing environment: Clinical 
guidelines note that a moist wound environment is ideal for wound 
healing. Wound dressings can provide this benefit based on their 
ability to absorb and manage wound exudate levels. Wound dressings may 
include ingredients that aid in moisture management, for example, 
through acting as a humectant to manage moisture levels within the 
dressing or forming a barrier to moisture loss.
     Providing effective barrier to environmental contaminants: 
This benefit applies to solid wound dressings that utilize either a 
mechanical barrier (e.g., polyurethane film layer) or an antimicrobial 
barrier to eliminate the penetration of external microorganisms through 
the dressing and into the wound.
     Reducing microbial growth within the dressing: This 
benefit applies to solid wound dressings that utilize an antimicrobial 
to reduce microbial growth and colonization of dressings, which can 
reduce soiling and degradation of a dressing and extend the length of 
time a dressing may be applied before needing to be changed.
     Extending the shelf life of nonsterile and/or multiuse 
wound dressings: This benefit applies to wound dressings formulated as 
a gel, cream, or ointment and liquid wound washes that utilize an 
antimicrobial as a preservative to reduce microbial growth within the 
product during shelf storage. This helps keep dressings from 
prematurely degrading or becoming a source of cross-contamination.
    Finally, it is noted that selection of certain wound dressings and 
liquid wound washes is based on wound bed characteristics, and due to 
their heterogenous nature, no single wound dressing or liquid wound 
wash is suitable for all types of wounds. As such, the robust number 
and diversity of wound dressings and liquid wound washes currently on 
the market provides an overall benefit of choice for healthcare 
professionals and other end users to select wound dressings and liquid 
wound washes that are tailored to the wound characteristics of a 
particular patient.

D. Proposed Classification and FDA's Findings

1. Level of AMR Concern and Medically Important Antimicrobials
    FDA is proposing the following risk-based paradigm for evaluating 
the level of AMR concern (high, medium, or low) associated with wound 
dressings and liquid wound washes containing antimicrobials discussed 
in this proposed classification rule. The proposed paradigm is based on 
a detailed characterization of the antimicrobials contained in wound 
dressings and liquid wound washes cleared by FDA under product codes 
FRO, GER, MGP, MGQ, and EFQ, and by relying on FDA's experience in this 
area, literature review, the 2005 and 2016 Panels' recommendations, and 
other available information.
    To evaluate the level of AMR concern and the proposed risk-based 
paradigm, a literature review was conducted to identify the following 
attributes: (1) current applications of the antimicrobial, (2) known 
resistance mechanisms, (3) if any of the resistance genes are plasmid-
mediated, (4) evidence of potential for coselection of medically 
important antimicrobial resistance via mechanisms such as coresistance 
or cross-resistance, and (5) known resistant microbial species. FDA is 
proposing to categorize certain wound

[[Page 83789]]

dressings and liquid wound washes as either having a high, medium, or 
low level of AMR concern, which then corresponds with the proposed 
classification of the wound dressings and liquid wound washes 
containing antimicrobials (as either being in class III or class II, 
based on the criteria in section 513(a)(1) of the FD&C Act).
2. Proposed Classification of Solid Wound Dressings Containing 
Antimicrobials and/or Other Chemicals (Proposed Sec.  878.4016)
    Based on FDA's experience with certain wound dressings, the 
collective 2005 and 2016 Panels' recommendations, and other available 
information, FDA is proposing to classify solid wound dressings 
containing medically important antimicrobials used as protectants (see 
table 2) into class III when intended to be used to cover and protect a 
wound, to absorb exudate, and to maintain appropriate moisture balance 
within the wound (proposed Sec.  878.4016(b)(1)). These wound dressings 
may additionally contain other chemicals (see table 3). FDA is 
proposing this classification as FDA believes that insufficient 
information exists to determine that general controls and special 
controls would provide reasonable assurance of safety and effectiveness 
for such wound dressings and these wound dressings present a potential 
unreasonable risk of illness or injury. FDA is also proposing, by 
proposed order published elsewhere in this issue of the Federal 
Register, to require the filing of a PMA if these wound dressings are 
classified into class III, which will only be finalized if FDA 
classifies such wound dressings as class III.
    In proposed Sec.  878.4016(b)(2), FDA is proposing to classify 
solid wound dressings containing antimicrobial(s) used as protectants 
with a medium or low level of AMR concern (see table 2) and/or other 
chemicals (see table 3) into class II (special controls). FDA is 
proposing this action based on the determination that general controls 
alone are not sufficient to provide reasonable assurance of the safety 
and effectiveness of these wound dressings, and there is sufficient 
information to establish special controls to provide such assurance.
    The special controls proposed in Sec.  878.4016(b)(2)(i) through 
(vii) for these proposed class II wound dressings include performance 
testing and descriptive information, antimicrobial characterization and 
performance testing, AMR risk assessment, biocompatibility evaluation, 
risk management assessment for animal-derived materials and/or 
botanical extracts, labeling, shelf life validation, and sterilization 
validation.
3. Proposed Classification for Wound Dressings Formulated as a Gel, 
Cream, or Ointment Containing Antimicrobials and/or Other Chemicals 
(Proposed Sec.  878.4017)
    Based on FDA's experience with certain wound dressings, the 
collective 2005 and 2016 Panels' recommendations, and other available 
information, FDA is proposing to classify wound dressings formulated as 
a gel, cream, or ointment containing medically important antimicrobials 
used as preservatives (see table 2), into class III when intended to 
maintain appropriate moisture balance within the wound (proposed Sec.  
878.4017(b)(1)). These wound dressings may additionally contain other 
chemicals (see table 3). FDA is proposing this classification as FDA 
believes that insufficient information exists to determine that general 
controls and special controls would provide reasonable assurance of the 
safety and effectiveness for such wound dressings and these wound 
dressings present a potential unreasonable risk of illness or injury. 
FDA is also proposing, by proposed order published elsewhere in this 
issue of the Federal Register, to require the filing of a PMA if these 
wound dressings are classified into class III, which will only be 
finalized if FDA classifies such wound dressings as class III.
    In proposed Sec.  878.4017(b)(2), FDA is proposing to classify 
wound dressings formulated as a gel, cream, or ointment containing 
antimicrobials used as preservatives with a medium or low level of AMR 
concern (see table 2) and/or other chemicals (see table 3) into class 
II (special controls). FDA is proposing this action based on the 
determination that general controls alone are not sufficient to provide 
reasonable assurance of the safety and effectiveness of these wound 
dressings, and there is sufficient information to establish special 
controls to provide such assurance.
    The special controls proposed in Sec.  878.4017(b)(2)(i) through 
(vii) include performance testing and descriptive information, 
antimicrobial characterization and preservative effectiveness testing, 
AMR risk assessment, biocompatibility evaluation, risk management 
assessment for animal-derived materials and/or botanical extracts, 
labeling, shelf-life validation, and sterilization validation.
4. Proposed Classification for Liquid Wound Washes (Proposed Sec.  
878.4019)
    Based on FDA's experience with certain wound dressings and liquid 
wound washes, the collective 2005 and 2016 Panels' recommendations, and 
other available information, FDA is proposing to classify liquid wound 
washes containing medically important antimicrobials used as 
preservatives (see table 2) into class III when intended to irrigate 
the wound and to moisten solid wound dressings to maintain appropriate 
moisture balance within the dressing (proposed Sec.  878.4019(b)(1)). 
These liquid wound washes may additionally contain other chemicals (see 
table 3). FDA is proposing this classification as it believes that 
insufficient information exists to determine that general controls and 
special controls would provide reasonable assurance of safety and 
effectiveness for such liquid wound washes and these washes present a 
potential unreasonable risk of illness or injury. FDA is also 
proposing, by proposed order published elsewhere in this issue of the 
Federal Register, to require the filing of a PMA if these liquid wound 
washes are classified into class III, which will only be finalized if 
FDA classifies such liquid wound washes as class III.
    In proposed Sec.  878.4018(b)(2), FDA is proposing to classify 
liquid wound washes containing antimicrobials used as preservatives 
with a medium or low level of AMR concern (see table 2) or other 
chemicals (see table 3) into class II (special controls). FDA is 
proposing this action based on the determination that general controls 
alone are not sufficient to provide reasonable assurance of the safety 
and effectiveness of these liquid wound washes and there is sufficient 
information to establish special controls to provide such assurance.
    The special controls proposed in Sec.  878.4018(b)(2)(i) through 
(vii) include performance testing and descriptive information, 
antimicrobial characterization and preservative effectiveness testing, 
AMR risk assessment, biocompatibility evaluation, risk management 
assessment for animal-derived materials and/or botanical extracts, 
labeling, shelf-life validation, and sterilization validation.
    In addition, if this proposed rule and classification is finalized, 
FDA plans to publish a notice in the Federal Register announcing its 
intent to exempt from the premarket notification requirements liquid 
wound washes containing water or 0.9 percent saline only, which do not 
contain antimicrobials, other chemicals,

[[Page 83790]]

or animal-derived materials, subject to certain limitations. FDA 
believes that a 510(k) is not necessary to provide reasonable assurance 
of the safety and effectiveness of this wound wash type, in accordance 
with section 510(m) of the FD&C Act.
5. Proposed Special Controls
    Based on the collective 2005 and 2016 Panels' recommendations, 
FDA's experience with these wound dressings and liquid wound washes, 
and other available information, FDA is proposing the special controls 
identified in this section for wound dressings and liquid wound washes 
that are proposed to be classified into class II. FDA believes that 
these special controls, in addition to general controls, are necessary 
to provide a reasonable assurance of safety and effectiveness of the 
wound dressings and liquid wound washes containing antimicrobials used 
as either protectants or preservatives with a medium or low level of 
AMR concern (see table 2) and/or other chemicals (see table 3). Special 
controls were discussed at the 2016 Panel (Ref. 2, see section III.B of 
the Executive Summary). The 2016 Panel agreed that the special controls 
as presented would provide a reasonable assurance of safety and 
effectiveness for these wound dressings and liquid wound washes, 
emphasizing in discussions, among other things, the need for adequate 
labeling, specific use claims, and sufficient data to support labeling 
claims.
    As noted in Section V.C Risks to Health and Public Health Benefits 
of this proposed rule, three risks (specifically, toxicity, 
transmission of pathogens and parasites, and immunological reaction) 
were added as separate risks since the 2016 Panel meeting, which 
resulted in changes to the corresponding proposed mitigation measures 
for the identified risks to health. Additionally, 2016 Panel members 
suggested we consider including leaching and systemic absorption of 
antimicrobials or other chemicals as risks. These risks are included 
within adverse tissue reaction and toxicity and mitigations are 
included to address them. However, FDA does not believe these need to 
be added as separate categories of risks to health.
    For several of the risks to health, additional mitigation measures 
are proposed compared to those identified during the 2016 Panel. The 
proposed mitigations are due to the specific attributes of the 
materials of the wound dressings and liquid wound washes, which require 
specific mitigation measures to address the risks identified (e.g., 
animal-derived materials, botanical extracts). The newly proposed 
mitigation measures include performance testing and descriptive 
information and a risk management assessment for animal-derived 
materials and/or botanical extracts. In addition, certain previously 
proposed mitigation measures (e.g., labeling, performance data) were 
recognized to have a role in mitigating more risks than initially 
proposed during the 2016 Panel meeting. Mitigations have been 
associated with the relevant identified risks as subsequently discussed 
in this proposed rule. Following the 2016 Panel meeting, an additional 
probable health risk was identified based on reports in the literature 
(Refs. 49-55) regarding the understood role that our skin microbiota 
plays in the wound healing cascade.
    As such, antimicrobials that leach from wound dressings may 
inadvertently impact the skin microbiota in the periwound area 
resulting in impaired wound healing. Antimicrobial preservative claims 
for wound dressings formulated as a gel, cream, or ointment and liquid 
wound washes; and protectant and microbial barrier claims for solid 
wound dressings may be supported by in vitro testing, limiting the 
stated period of effectiveness to that supported by simulated-use 
testing parameters, as described in the special controls in section V.D 
of this proposed rule.
    FDA believes that the special controls proposed for these wound 
dressings and liquid wound washes, in addition to the general controls, 
mitigate the risks to health discussed in Section V.C, Risks to Health 
and Public Health Benefits of this proposed rule and are necessary to 
provide reasonable assurance of safety and effectiveness. Tables 4-6 
depict how each identified risk to health would be mitigated by the 
proposed special controls.

Table 4--Identified Risks to Health and Proposed Mitigation Measures for
  Solid Wound Dressings Containing Antimicrobials With a Medium or Low
Level of AMR Concern for Protectant Purposes Only and/or Other Chemicals
------------------------------------------------------------------------
       Identified risks to health         Proposed mitigation measure(s)
------------------------------------------------------------------------
Adverse tissue reaction................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Immunological reaction.................   Performance testing
                                          and descriptive information.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Transmission of pathogens and parasites   Performance testing
 (e.g., bacteria, mycoplasma, fungi,      and descriptive information.
 viruses, and other transmissible         Risk management
 spongiform encephalopathy agents).       assessment for the inclusion
                                          of animal-derived material.
                                          Labeling.
Toxicity...............................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Delayed wound healing..................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Labeling.
Incompatibilities with other therapies.   Labeling.

[[Page 83791]]

 
Contribution to the spread of             Antimicrobial
 antimicrobial resistance (AMR).          Characterization and
                                          Performance Testing.
                                          AMR risk assessment.
                                          Labeling.
Infection..............................   Antimicrobial
                                          Characterization and
                                          Performance Testing.
                                          Shelf life validation.
                                          Sterilization
                                          validation.
                                          Risk management
                                          assessment for animal-derived
                                          materials and/or botanical
                                          extracts.
                                          Labeling.
Microbial growth within the product       Antimicrobial
 during use.                              Characterization and
                                          Performance Testing.
                                          Sterilization
                                          validation.
Product degradation during stated shelf   Shelf life validation.
 storage.                                 Labeling.
Retention of dressing material in wound   Performance testing
                                          and descriptive information.
                                          Labeling.
Loss of Barrier function...............   Antimicrobial
                                          Characterization and
                                          Performance Testing.
Negatively impacting the skin             Antimicrobial
 microbiota in the periwound area         Characterization and
 resulting in impaired wound healing.     Performance Testing.
                                          Labeling.
------------------------------------------------------------------------


Table 5--Identified Risks to Health and Proposed Mitigation Measures for
   Wound Dressings Formulated as a Gel, Cream, or Ointment Containing
      Antimicrobials With a Medium or Low Level of AMR Concern for
            Preservative Purposes Only and/or Other Chemicals
------------------------------------------------------------------------
       Identified risks to health         Proposed mitigation measure(s)
------------------------------------------------------------------------
Adverse tissue reaction................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Immunological reaction.................   Performance testing
                                          and descriptive information.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Transmission of pathogens and parasites   Performance testing
 (e.g., bacteria, mycoplasma, fungi,      and descriptive information.
 viruses, and other transmissible         Risk management
 spongiform encephalopathy agents).       assessment for the inclusion
                                          of animal-derived material.
                                          Labeling.
Toxicity...............................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Delayed wound healing..................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Labeling.
Incompatibilities with other therapies.   Labeling.
Contribution to the spread of             Antimicrobial
 antimicrobial resistance (AMR).          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          AMR risk assessment.
                                          Labeling.
Infection..............................   Antimicrobial
                                          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          Shelf life validation.
                                          Sterilization
                                          validation.
                                          Risk management
                                          assessment for animal-derived
                                          materials and/or botanical
                                          extracts.
                                          Labeling.
Microbial growth within the product       Antimicrobial
 during storage.                          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          Sterilization
                                          validation.
Product degradation during stated shelf   Shelf life validation.
 storage.                                 Labeling.
Negatively impacting the skin             Antimicrobial
 microbiota in the periwound area         Characterization and
 resulting in impaired wound healing.     Performance Testing.
                                          Labeling.
------------------------------------------------------------------------


[[Page 83792]]


Table 6--Identified Risks to Health and Proposed Mitigation Measures for
Liquid Wound Washes Containing Antimicrobials With a Medium or Low Level
 of AMR Concern for Preservative Purposes Only, and/or Containing Other
                                Chemicals
------------------------------------------------------------------------
       Identified risks to health         Proposed mitigation measure(s)
------------------------------------------------------------------------
Adverse tissue reaction................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Immunological reaction.................   Performance testing
                                          and descriptive information.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Transmission of pathogens and parasites   Performance testing
 (e.g., bacteria, mycoplasma, fungi,      and descriptive information.
 viruses, and other transmissible         Risk management
 spongiform encephalopathy agents).       assessment for the inclusion
                                          of animal-derived material.
                                          Labeling.
Toxicity...............................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Risk management
                                          assessment for the inclusion
                                          of animal-derived material and/
                                          or botanical extracts.
                                          Labeling.
Delayed wound healing..................   Performance testing
                                          and descriptive information.
                                          Biocompatibility
                                          evaluation.
                                          Labeling.
Incompatibilities with other therapies.   Labeling.
Contribution to the spread of             Antimicrobial
 antimicrobial resistance (AMR).          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          AMR risk assessment.
                                          Labeling.
Infection..............................   Antimicrobial
                                          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          Shelf life validation.
                                          Sterilization
                                          validation.
                                          Risk management
                                          assessment for animal-derived
                                          materials and/or botanical
                                          extracts.
                                          Labeling.
Microbial growth within the product       Antimicrobial
 during storage.                          Characterization and
                                          Preservative Effectiveness
                                          Testing.
                                          Sterilization
                                          validation.
Product degradation during stated shelf   Shelf life validation.
 storage.
                                          Labeling.
Inability to remove wound debris and      Performance testing
 foreign materials.                       and descriptive information.
                                          Labeling.
Negatively impacting the skin             Antimicrobial
 microbiota in the periwound area         Characterization and
 resulting in impaired wound healing.     Performance Testing.
                                          Labeling.
------------------------------------------------------------------------

VI. Proposed Effective/Compliance Dates

    FDA proposes that any final rule, based on this proposed rule, 
become effective 30 days after its date of publication in the Federal 
Register.
    Below, FDA has laid out a proposed tiered approach that we believe 
will help ensure the efficient and effective implementation of this 
classification regulation, when finalized.

A. Devices That Are Proposed To Be Classified Into Class III

    For devices proposed to be classified into class III in this 
proposed rule, FDA is publishing a proposed order to require the filing 
of a PMA elsewhere in this issue of the Federal Register.
    If this proposed rule and related proposed order to require the 
filing of a PMA are finalized, wound dressings and liquid wound washes 
that are proposed to be classified into class III are considered 
adulterated if a PMA is not filed with FDA within 30 months after the 
classification of the device into class III, and commercial 
distribution of the product must cease (see section 501(f)(2)(B) of the 
FD&C Act (21 U.S.C. 351(f)(2)(B))).
    Moreover, manufacturers must cease distribution of devices upon 
receiving a not approvable or denial decision rendered on a PMA. In 
such circumstances, to resume distribution, these manufacturers must 
receive PMA approval for their devices. However, the product may be 
distributed for investigational use only if the requirements of the 
investigational device exemptions regulations in 21 CFR part 812 are 
met.
    For currently marketed wound dressings and liquid wound washes that 
are proposed to be classified into class III, FDA is proposing in the 
above-mentioned proposed order that it does not intend to enforce 
compliance with the 30-month deadline by which PMAs must be submitted 
when a notice of intent to file a PMA is submitted within 90 days of 
the effective date of the order, if finalized. In circumstances when a 
notice of intent to file is submitted, FDA is proposing that it does 
not intend to enforce compliance with the 30-month deadline by which 
PMAs must be submitted when a PMA is submitted within 90 days after the 
30-month deadline. However, as discussed above, even if a notice of 
intent and PMA are submitted by these dates, manufacturers must cease 
distribution of devices upon

[[Page 83793]]

receiving a not approvable or denial decision rendered on a PMA.

B. Devices That Are Proposed To Be Classified Into Class II

     Devices proposed to be classified into class II that have 
not been offered for sale prior to the effective date of this rule, 
when finalized, or have been offered for sale but are required to 
submit a new 510(k) under Sec.  [thinsp]807.81(a)(3): FDA proposes that 
before marketing these devices, manufacturers would have to obtain 
510(k) clearance (unless exempted from 510(k)), and demonstrate 
compliance with the applicable special controls, within 6 months after 
the effective date of this rule, when finalized. After that date, if a 
manufacturer markets such a device without receiving 510(k) clearance, 
then FDA would consider taking action against such a manufacturer under 
its usual enforcement policies.
     Devices proposed to be classified into class II that have 
prior 510(k) clearance: FDA proposes that it would accept a new 510(k) 
and would issue a new clearance letter, as appropriate, indicating 
substantial equivalence and compliance with the special controls. These 
devices could serve as predicates for new devices. These clearance 
letters would be made publicly available in FDA's 510(k) database, and 
compliance with special controls at the time of clearance would be 
stated in the publicly available 510(k) Summary posted in this 
database. FDA believes that our public database is a transparent tool 
allowing consumers to confirm that their devices have been submitted 
under a new 510(k) and demonstrate compliance with the applicable 
special controls.
    For the devices proposed to be classified into class II, subject to 
special controls as described in this proposed rule, FDA proposes that 
the special controls become effective 6 months after the effective date 
of the rule, when finalized. FDA proposes that if a manufacturer 
markets such a device 6 months after the effective date of the rule, 
when finalized, and that device does not comply with the special 
controls, then FDA would consider taking action against such a 
manufacturer under its usual enforcement policies.

VII. Preliminary Economic Analysis of Impact

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, Executive Order 14094, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4).
    Executive Orders 12866, 13563, and 14094 direct us to assess all 
benefits, costs, and transfers of available regulatory alternatives 
and, when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). Rules are ``significant'' under Executive Order 12866 
Section 3(f)(1) (as amended by Executive Order 14094) if they ``have an 
annual effect on the economy of $200 million or more (adjusted every 3 
years by the Administrator of the Office of Information and Regulatory 
Affairs (OIRA) for changes in gross domestic product); or adversely 
affect in a material way the economy, a sector of the economy, 
productivity, competition, jobs, the environment, public health or 
safety, or State, local, territorial, or tribal governments or 
communities.'' OIRA has determined that this proposed rule is not a 
significant regulatory action under Executive Order 12866, section 
3(f)(1).
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the costs of the proposed rule primarily accrue to 
larger firms, we propose to certify that the proposed rule will not 
have a significant economic impact on a substantial number of small 
entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes estimates of 
anticipated impacts, before proposing ``any rule that includes any 
Federal mandate that may result in the expenditure by State, local, and 
tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $177 
million, using the most current (2022) Implicit Price Deflator for the 
Gross Domestic Product. This proposed rule would not result in an 
expenditure in any year that meets or exceeds this amount.
    This proposed rule, if finalized, would classify certain types of 
currently unclassified wound dressings and liquid wound washes 
containing antimicrobials and/or other chemicals: solid dressings; 
wound dressings formulated as a gel, cream, or ointment; and liquid 
wound washes. FDA is proposing to classify wound dressings and liquid 
wound washes containing medically important antimicrobials into class 
III due to their high level of AMR concern, for which FDA is separately 
proposing to require the filing of a PMA. FDA has determined that 
general controls and special controls together are insufficient to 
provide reasonable assurance of safety and effectiveness for such wound 
dressings and liquid wound washes. In addition, FDA is proposing to 
classify wound dressings and liquid wound washes containing 
antimicrobials with a medium or low level of AMR concern into class II 
subject to general and special controls. FDA is publishing this 
proposed rule based, in part, on the recommendations of the General and 
Plastic Surgery Devices Panel regarding the classification of certain 
types of wound dressings and liquid wound washes.
    To estimate costs and benefits associated with the proposed rule, 
if finalized, we assume that the appropriate baseline is the current 
state of the United States with unclassified wound dressings and liquid 
wound washes containing antimicrobials and/or other chemicals. We then 
compare the likely impacts of the proposed rule against this baseline. 
The quantifiable benefits of the proposed rule, if finalized, accrue to 
manufacturers of wound dressings and liquid wound washes and FDA. These 
benefits are the result of clarifications in the 510(k) submission 
process, specifically defined regulatory classification, and published 
special controls. This additional clarity in requirements should result 
in fewer additional information submissions to FDA.
    We estimate annualized cost savings ranging from approximately 
$1.12 million to $6.31 million at a 3 percent discount rate, and 
approximately $1.14 million to $6.42 million at a 7 percent discount 
rate. Our primary annualized estimates are approximately $2.66 million 
at a 3 percent discount rate and $2.71 million at a 7 percent discount 
rate. The primary estimates of the present value of total cost savings 
in the 10 years following any final rule that may be issued based on 
this proposed rule are $24.55 million at a 3 percent rate of discount 
and $19.02 million at a 7 percent rate of discount. If the proposed 
rule is finalized, society may experience welfare gains from reductions 
in AMR due to the rule. These welfare gains would be in the form of 
decreased mortality, morbidity, and medical costs. Unfortunately, the 
magnitude of these potential benefits is difficult to forecast, and we 
do not quantify these impacts in the analysis. We summarize quantified 
benefits in table 7.

[[Page 83794]]

    The costs of the proposed rule, if finalized, are associated with 
costs to industry for reading and understanding the rule, preparing and 
submitting PMAs, and other costs related to the PMA process and 
maintaining the class III designation. FDA also incurs costs from 
reviewing PMAs, annual and supplemental reports, and inspection 
activities. When annualized over a period of 10 years, we estimate 
these costs range from approximately $0.72 million to $1.25 million at 
a 3 percent discount rate, and approximately $0.65 million to $1.17 
million at a 7 percent discount rate. Our primary annualized estimates 
are approximately $0.92 million at a 3 percent discount rate and $0.85 
million at a 7 percent discount rate. The primary estimates of the 
present value of total costs in the 10 years following any final rule 
that may be issued based on the proposed rule are approximately $7.23 
million at a 3 percent discount rate and $6.48 million at a 7 percent 
discount rate. These values are summarized in table 7.

                Table 7--Summary of Benefits, Costs, and Distributional Effects of Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                                                                  Units
                                                                  ------------------------------------
           Category              Primary       Low        High                               Period      Notes
                                estimate    estimate    estimate      Year      Discount     covered
                                                                     dollars    rate (%)     (years)
----------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized            $2.71       $1.14       $6.42        2022           7          10
     $millions/year.                 2.66        1.12        6.31        2022           3          10
    Annualized Quantified....  ..........  ..........  ..........  ..........           7  ..........
                               ..........  ..........  ..........  ..........           3  ..........
                              ----------------------------------------------------------------------------------
    Qualitative..............
 
----------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized             0.92        0.72        1.25        2022           7          10
     $millions/year.                 0.85        0.65        1.17        2022           3          10
    Annualized Quantified....  ..........  ..........  ..........  ..........           7  ..........
                               ..........  ..........  ..........  ..........           3  ..........
                              ----------------------------------------------------------------------------------
    Qualitative..............
 
----------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized         ..........  ..........  ..........  ..........           7  ..........
     Monetized $millions/year. ..........  ..........  ..........  ..........           3  ..........
                              ----------------------------------------------------------------------------------
    From/To..................  From:
                               To:
                              ----------------------------------------------------------------------------------
    Other Annualized                 0.30        0.19        0.58        2022           7          10
     Monetized $millions/year.       0.28        0.18        0.56        2022           3          10
                              ----------------------------------------------------------------------------------
    From/To..................  From: Industry
                               To: FDA
----------------------------------------------------------------------------------------------------------------
Effects:
    State, Local, or Tribal Government: None....................................................................
    Small Business: None........................................................................................
    Wages:......................................................................................................
    Growth:.....................................................................................................
----------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 56) and at https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.34(b) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no 
collection of information. Therefore, clearance by the Office of 
Management and Budget under the Paperwork Reduction Act of 1995 is not 
required.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
this proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we conclude that the rule does not contain policies that have 
federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect on one or more Indian Tribes, on the 
relationship between the Federal Government and Indian Tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian Tribes. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between

[[Page 83795]]

9 a.m. and 4 p.m., Monday through Friday; they also are available 
electronically at https://www.regulations.gov. References without 
asterisks are not on public display at https://www.regulations.gov 
because they have copyright restriction. Some may be available at the 
website address, if listed. References without asterisks are available 
for viewing only at the Dockets Management Staff. FDA has verified the 
website addresses, as of the date this document publishes in the 
Federal Register, but websites are subject to change over time.

*1. General and Plastic Surgery Devices Panel, ``Transcript of the 
FDA General and Plastic Surgery Devices Panel meeting--November 17, 
1998.'' Available at https://web.archive.org/web/20180125235924/https://www.fda.gov/ohrms/dockets/ac/98/transcpt/3483t1.pdf.
*2. General and Plastic Surgery Devices Panel, ``Brief Summary from 
the General and Plastic Surgery Devices Panel Meeting--August 25-26, 
2005.'' Available at https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/GeneralandPlasticSurgeryDevicesPanel/ucm124755.htm.
*3. General and Plastic Surgery Devices Panel, ``2016 Meeting 
Materials of the General and Plastic Surgery Advisory Panel--
September 20-21, 2016.'' Available at https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/GeneralandPlasticSurgeryDevicesPanel/ucm518493.htm.
4. WHO, ``Critically Important Antimicrobials For Human Medicine: 
6th Revision,'' 2018. Available at https://www.who.int/publications/i/item/9789241515528.
5. Sen C., G. Gordillo, S. Roy, et al., ``Human Skin Wounds: A Major 
and Snowballing Threat to Public Health and the Economy,'' Wound 
Repair and Regeneration, 17(6):763-771, 2009. Available at https://doi.org/10.1111/j.1524-475X.2009.00543.x.
6. Nussbaum S., M. Carter, C. Fife, et al., ``An Economic Evaluation 
of the Impact, Cost, and Medicare Policy Implications of Chronic 
Nonhealing Wounds,'' Value in Health, 21(1):27-32, 2018. Available 
at https://doi.org/10.1016/j.jval.2017.07.007.
7. Berry C., D.R. Murdoch, and J.J. McMurray, ``Economics of Chronic 
Heart Failure,'' European Journal of Heart Failure, 3(3):283-291, 
2001. Available at https://doi.org/10.1016/S1388-9842(01)00123-4.
8. Carter M., C. Fife, D. Walker, et al., ``Estimating the 
Applicability of Wound Care Randomized Controlled Trials to General 
Wound-Care Populations by Estimating the Percentage of Individuals 
Excluded from a Typical Wound-Care Population in Such Trials,'' 
Advances in Skin & Wound Care, 22(7):316-324, 2009. Available at 
https://doi.org/10.1097/01.asw.0000305486.06358.e0.
9. Kuhn A., S.J. Coulter, ``Balancing Ulcer Cost and Quality 
Equation,'' Nursing Economics, 10(5):353-359, 1992. Available at 
https://pubmed.ncbi.nlm.nih.gov/1465158/.
10. Hess C.T., ``Putting the Squeeze on Venous Ulcers,'' Nursing, 
34(14), 8-13, 2004. Available at http://dx.doi.org/10.1097/00152193-200411001-00008.
11. Driver V., M. Fabbi, L. Lavery, et al., ``The Costs of Diabetic 
Foot: The Economic Case for the Limb Salvage Team,'' Journal of 
Vascular Surgery, 52(3 Suppl), 17S-22S, 2010. Available at https://doi.org/10.1016/j.jvs.2010.06.003.
12. Gordon M., M. Gottschlich, E. Helvig, et al., ``Review of 
Evidence-Based Practice for the Prevention of Pressure Sores in Burn 
Patients,'' Journal of Burn Care & Research, 25(5):388-410, 2004. 
Available at https://doi.org/10.1097/01.BCR.0000138289.83335.F4.
13. Guo S. and L.A. DiPietro, ``Factors Affecting Wound Healing,'' 
Journal of Dental Research, 89(3):219-229, 2010. Available at 
https://doi.org/10.1177/0022034509359125.
14. Gottrup F., J. Apelqvist, T. Bjarnsholt, et al., 
``Antimicrobials and Non-Healing Wounds: Evidence, Controversies, 
and Suggestions--Key Messages,'' Journal of Wound Care, 23(10):477-
478, 480, 482, 2014. Available at https://doi.org/10.12968/jowc.2014.23.10.477.
15. Sen, C., ``Human Wounds and Its Burden: An Updated Compendium of 
Estimates,'' Advances in Wound Care, 8(2):39-48, 2019. Available at 
https://doi.org/10.1089/wound.2019.0946.
*16. FDA, ``Supporting Antimicrobial Stewardship in Veterinary 
Settings: Goals for Fiscal Years 2024-2028: Key Phase 3 and Key 
Phase 4 Actions,'' September 2023. Available at https://www.fda.gov/media/172347/download?attachment.
17. Hutchings M., A. Truman, and B. Wilkinson, ``Antibiotics: Past, 
Present and Future,'' Current Opinion in Microbiology, 51:72-80, 
2019. Available at https://doi.org/10.1016/j.mib.2019.10.008.
*18. CDC, Antibiotic Resistance Threats in the United States 2019 
Report. Available at https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.
19. Smith R. and J. Coast, ``The True Cost of Antimicrobial 
Resistance,'' The British Medical Journal, 10(1493):1-5, 2013. 
Available at https://doi.org/10.1136/bmj.f1493; See also Dadgostar 
P., ``Antimicrobial Resistance: Implications and Costs.,'' Infection 
and Drug Resistance, 12:3903-3910, 2019. Available at https://doi.org/10.2147/IDR.S234610.
20. National Quality Forum, ``NQF, CDC Issue Guidance To Help 
Hospitals Better Manage Use of Antibiotics,'' 2016. Available at 
https://www.qualityforum.org/News_And_Resources/Press_Releases/2016/NQF_CDC_Issue_Guidance_to_Help_Hospitals_Better_Manage_Use_of_Antibiotics.aspx.
*21. CDC, The Core Elements of Hospital Antibiotic Stewardship 
Programs: 2019. Available at https://www.cdc.gov/antibiotic-use/healthcare/pdfs/hospital-core-elements-H.pdf.
*22. HHS, ``Antimicrobial Resistance.'' Available at https://www.hhs.gov/about/agencies/oga/global-health-security/antimicrobial-resistance/index.html (last accessed on July 29, 2022).
23. Munita J. and C. Arias, ``Mechanisms of Antibiotic Resistance,'' 
Microbiology Spectrum, 4(2), 1-37, 2016. Available at https://doi.org/10.1128/microbiolspec.VMBF-0016-2015.
24. Bennett, P.M., ``Plasmid Encoded Antibiotic Resistance: 
Acquisition and Transfer of Antibiotic Resistance Genes in 
Bacteria,'' British Journal of Pharmacology, 153(Suppl 1), S347-
S357, 2008. Available at https://doi.org/10.1038/sj.bjp.0707607.
25. Chandan P., J. Bengtsson-Palme, E. Kristiansson, et al., ``Co-
Occurrence of Resistance Genes to Antibiotics, Biocides and Metals 
Reveals Novel Insights into Their Co-Selection Potential,'' BMC 
Genomics, 16(964), 1-14, 2015. Available at https://doi.org/10.1186/s12864-015-2153-5.
26. Peleg A., and D. Hooper. ``Hospital-Acquired Infections Due to 
Gram-Negative Bacteria,'' The New England Journal of Medicine, 
362(19):1804-1813, 2010. Available at https://doi.org/10.1056/FNEJMra0904124.
27. WHO, ``Burns.'' Available at https://www.who.int/mediacentre/factsheets/fs365/en/ (last accessed on July 29, 2022).
*28. FDA, ``Evaluating the Safety of Antimicrobial New Animal Drugs 
With Regard to Their Microbiological Effects on Bacteria of Human 
Health Concern: Guidance for Industry,'' October 23, 2003. Available 
at https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052519.pdf.
29. Government of Canada, ``Categorization of Antimicrobial Drugs 
Based on Importance in Human Medicine,'' 2009. Available at https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/antimicrobial-resistance/categorization-antimicrobial-drugs-based-importance-human-medicine.html.
30. McDonnell G., and A. Russell, ``Antiseptic and Disinfectants: 
Activity, Action, and Resistance,'' Clinical Microbiology Reviews, 
12(1), 147-179, 1999. Available at https://doi.org/10.11282Fcmr.12.1.147.
31. Linehanm J., O. Harrison, S. Han, et al., ``Non-Classical 
Immunity Controls Microbiota Impact on Skin Immunity and Tissue 
Repair,'' Cell, 172(4), 784-796.e18, 2018. Available at https://doi.org/10.1016/j.cell.2017.12.033.
32. Johnson T., B. Gomez, M. McIntyre, et al., ``The Cutaneous 
Microbiome and Wounds: New Molecular Targets To Promote Wound 
Healing,'' International

[[Page 83796]]

Journal of Molecular Sciences, 19 (9), 2699, 2018. Available at 
https://doi.org/10.3390/ijms19092699.
33. Leonel C., I. Sena, W. Silva, et al., ``Staphylococcus 
Epidermidis Role in the Skin Microenvironment,'' Journal of Cellular 
And Molecular Medicine, 23(9), 5949-5955, 2019. Available at https://doi.org/10.1111/jcmm.14415.
34. Pastar I., K. O'Neill, L. Padula, et al., ``Staphylococcus 
Epidermidis Boosts Innate Immune Response by Activation of Gamma 
Delta T Cells and Induction of Perforin-2 in Human Skin,'' Frontiers 
in Immunology, 11, 550946, 2020. Available at https://doi.org/10.3389/fimmu.2020.550946.
35. Luqman A., M. Muttaqin, S. Yulaipi, et al., ``Trace Amines 
Produced by Skin Bacteria Accelerate Wound Healing in Mice,'' 
Communications Biology, 3, 277, 2020. Available at https://doi.org/10.1038/s42003-020-1000-7.
36. Brown M., A. Horswill, ``Staphylococcus Epidermidis--Skin Friend 
or Foe?'' PLOS Pathogens, 16(11):e1009026, 2020. Available at 
https://doi.org/10.1371/journal.ppat.1009026.
37. Burke T., M. Rupp, P. Fey, ``Staphylococcus Epidermidis,'' 
Trends in Microbiology, 763-764, 2023. Available at https://doi.org/10.1016/j.tim.2023.01.001.
*38. FDA, ``Classification of Products as Drugs and Devices & 
Additional Product Classification Issues: Guidance for Industry and 
FDA Staff,'' September 2017. Available at https://www.fda.gov/media/80384/download.
*39. FDA, ``General and Plastic Surgery Devices; Classification of 
the Nonresorbable Gauze/Sponge for External Use, the Hydrophilic 
Wound Dressing, the Occlusive Wound Dressing, and the Hydrogel Wound 
Dressing,'' 64 FR 53927, October 5, 1999. Available at https://www.gpo.gov/fdsys/pkg/FR-1999-10-05/pdf/99-25791.pdf.
*40. FDA, ``Medical Devices; Plastic Surgery Devices; Classification 
of Wound Dressing With Poly (Diallyl Dimethyl Ammonium Chloride) 
Additive,'' 74 FR 53165, October 16, 2009. Available at https://www.govinfo.gov/content/pkg/FR-2009-10-16/pdf/E9-24963.pdf.
41. Choi Y., K. Campbell, C. Levek, et al., ``Antibiotic Ointment 
Versus a Silver-Based Dressing for Children With Extremity Burns: A 
Randomized Controlled Study,'' Journal of Pediatric Surgery, 54(7), 
1391-1396, 2019. Available at https://pubmed.ncbi.nlm.nih.gov/29983189/.
42. Benedetto A., J. Staidle, J. Schoenfeld, et al., ``Comparing the 
Use of a Novel Antibiotic-Free Film-Forming Topical Wound Dressing 
Versus a Topical Triple Antibiotic in Dermatologic Surgical 
Procedures Including Mohs Micrographic Surgery,'' Journal of 
European Academy of Dermatology and Venereology, 35(1), 247-255, 
2021. Available at https://pubmed.ncbi.nlm.nih.gov/32978842/.
43. Kim D., W. Namen Ii, J. Moore, et al., ``Clinical Assessment of 
a Biofilm-disrupting Agent for the Management of Chronic Wounds 
Compared With Standard of Care: A Therapeutic Approach,'' Wounds, 
30(5), 120-130, 2018. Available at https://pubmed.ncbi.nlm.nih.gov/29521641/.
44. Connery S., J. Yankowitz, L. Odibo, et al., ``Effect of Using 
Silver Nylon Dressings To Prevent Superficial Surgical Site 
Infection After Cesarean Delivery: A Randomized Clinical Trial,'' 
American Journal of Obstetrics and Gynecology, 221(1):57.e1-57.e7, 
2019. Available at https://pubmed.ncbi.nlm.nih.gov/30849351/.
45. Ahmad H., K. Kallies, and S. Shapiro, ``The Effect of Mupirocin 
Dressings on Postoperative Surgical Site Infections in Elective 
Colorectal Surgery: A Prospective, Randomized Controlled Trial,'' 
The American Journal of Surgery, 217(6), 1083-1088, 2019. Available 
at https://pubmed.ncbi.nlm.nih.gov/30528317/.
46. Serena T., L. Serena, O. Al-Jalodi, et al., ``The Efficacy of 
Sodium Hypochlorite Antiseptic: A Double-Blind, Randomised 
Controlled Pilot Study,'' Journal of Wound Care, 31(Sup2), S32-s35, 
2022. Available at https://pubmed.ncbi.nlm.nih.gov/35148643/.
47. Saad A., E. Salazar, L. Allen, et al., ``Antimicrobial Dressing 
Versus Standard Dressing in Obese Women Undergoing Cesarean 
Delivery: A Randomized Controlled Trial,'' American Journal of 
Perinatology, 39(9), 951-958, 2022. Available at https://pubmed.ncbi.nlm.nih.gov/33264808/.
48. Dissemond J., J. Steinmann, K. M[uuml]nter, et al., ``Risk and 
Clinical Impact of Bacterial Resistance/Susceptibility to Silver-
Based Wound Dressings: A Systematic Review,'' Journal of Wound Care, 
29(4), 221-234, 2020. Available at https://pubmed.ncbi.nlm.nih.gov/32281507/.
49. Linehanm J., O. Harrison, S. Han, et al., ``Non-Classical 
Immunity Controls Microbiota Impact on Skin Immunity and Tissue 
Repair,'' Cell, 172(4), 784-796.e18, 2018. Available at https://pubmed.ncbi.nlm.nih.gov/29358051/.
50. Johnson T., B. Gomez, M. McIntyre, et al., ``The Cutaneous 
Microbiome and Wounds: New Molecular Targets To Promote Wound 
Healing,'' International Journal of Molecular Science, 19(9), 2699, 
2018. Available at https://doi.org/10.3390/ijms19092699.
51. Leonel C., I. Sena, W. Silva, et al., ``Staphylococcus 
Epidermidis Role in the Skin Microenvironment,'' Journal of Cellular 
and Molecular Medicine, 23(9), 5949-5955, 2019. Available at https://doi.org/10.1111/jcmm.14415.
52. Pastar I., K. O'Neill, L. Padula, et al., ``Staphylococcus 
Epidermidis Boosts Innate Immune Response by Activation of Gamma 
Delta T Cells and Induction of Perforin-2 in Human Skin,'' Frontiers 
in Immunology, 11, 550946, 2020. Available at https://doi.org/10.3389/fimmu.2020.550946.
53. Luqman A., M. Muttaqin, S. Yulaipi, et al., ``Trace Amines 
Produced by Skin Bacteria Accelerate Wound Healing in Mice,'' 
Communications Biology, 3, 277, 2020. Available at https://doi.org/10.1038/s42003-020-1000-7.
54. Brown M., A. Horswill, ``Staphylococcus Epidermidis--Skin Friend 
or Foe?'' PLOS Pathogens, 16(11):e1009026, 2020. Available at 
https://doi.org/10.1371/journal.ppat.1009026.
55. Burke T., M. Rupp, P. Fey, ``Staphylococcus Epidermidis,'' 
Trends in Microbiology, 2023. Available at https://doi.org/10.1016/j.tim.2023.01.001.
*56. FDA's full preliminary analysis of economic impacts is 
available in the Docket No. FDA-2023-N-3392 for this proposed rule 
and at https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

List of Subjects in 21 CFR Part 878

    Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, we propose 
that 21 CFR part 878 be amended as follows:

PART 878--GENERAL AND PLASTIC SURGERY DEVICES

0
1. The authority citation for part 878 continues to read as follows:

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. Add Sec.  878.4016 to subpart E to read as follows:


Sec.  878.4016  Solid wound dressings containing antimicrobials and/or 
other chemicals.

    (a) Identification. A solid wound dressing containing 
antimicrobials and/or other chemicals that are in a category listed in 
paragraph (a)(2) of this section is used to cover and protect a wound, 
to absorb exudate, and to maintain appropriate moisture balance within 
the wound and is intended for use only on external cutaneous (skin) 
wounds. The solid wound dressing materials are resorbable or 
nonresorbable, synthetic or naturally derived materials (including 
animal-derived materials such as collagen or chitosan), which are 
provided sterile in a form able to hold structural integrity 
temporarily or permanently. This regulation does not include a solid 
wound dressing that contains only animal-derived materials without the 
presence of antimicrobials and/or other chemicals.
    (1) Antimicrobials are used for protectant purposes only 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;

[[Page 83797]]

    (2) Categories of other chemicals are wound protectants, honey, 
synthetic peptides, or botanical extracts.
    (b) Classification. (1) Class III (premarket approval) for solid 
wound dressings that are identified in paragraph (a) of this section 
and that contain one or more medically important antimicrobials acting 
as protectants.
    (i) Date premarket approval application is required. A PMA is 
required to be filed with the Food and Drug Administration on or before 
[DATE OF THE LAST DAY OF THE 30TH FULL CALENDAR MONTH AFTER EFFECTIVE 
DATE OF FINAL RULE], for any solid wound dressing, as identified in 
paragraph (a) of this section, that either contains one or more 
medically important antimicrobials acting as protectants and was in 
commercial distribution before May 28, 1976, or has, on or before [DATE 
OF THE LAST DAY OF THE 30TH FULL CALENDAR MONTH AFTER EFFECTIVE DATE OF 
FINAL RULE], been found to be substantially equivalent to any solid 
wound dressing, as identified in paragraph (a) of this section, that 
contains one or more medically important antimicrobials and that was in 
commercial distribution before May 28, 1976. Any other solid wound 
dressing, as identified in paragraph (a) of this section, that contains 
one or more medically important antimicrobials shall have an approved 
PMA in effect before being placed in commercial distribution.
    (ii) [Reserved]
    (2) Class II (special controls) for solid wound dressings that are 
identified in paragraph (a) of this section and that contain one or 
more antimicrobials acting as protectants with a medium or low level of 
antimicrobial resistance (AMR) concern and/or other chemicals. The 
special controls are:
    (i) Performance testing and descriptive information. Performance 
testing and descriptive information must demonstrate the functionality 
of the solid wound dressing to achieve the specified use, including:
    (A) The physical and chemical characteristics of the solid wound 
dressing must be established. The following must be provided:
    (1) Identity, quantification, and purpose of each component in the 
finished product;
    (2) Specifications and characterization of each component in the 
finished product;
    (3) Demonstration that each component has a purpose and is present 
in appropriate amounts to perform as intended under anticipated 
conditions of use, including evaluation of expected worst-case 
conditions; and
    (4) Final release specifications for the manufactured solid wound 
dressing.
    (B) The solid wound dressing must be demonstrated to be sterile and 
the sterilization process must be validated.
    (C) The solid wound dressing must be demonstrated to be 
biocompatible.
    (D) Bench performance testing data must demonstrate that the solid 
wound dressing performs as intended under anticipated conditions of 
use, including evaluation of expected worst-case conditions.
    (E) Performance data must support the shelf life of the solid wound 
dressing by demonstrating package integrity and product functionality 
over the identified shelf life.
    (ii) Antimicrobial characterization and performance testing. For 
solid wound dressings containing antimicrobials with a medium or low 
level of AMR concern, antimicrobial characterization and performance 
testing must address the following:
    (A) Performance data must demonstrate that the antimicrobial has a 
purpose and is present in appropriate amounts to perform as intended 
under anticipated conditions of use and storage conditions, including 
evaluation of worst-case conditions. If the antimicrobial is present as 
a microbial barrier to cover and protect a wound, microbial barrier 
testing must be conducted to demonstrate elimination of passage of 
microorganisms through the solid wound dressing. If the antimicrobial 
is present to inhibit microbial growth within the solid wound dressing 
being used to cover and protect a wound, antimicrobial effectiveness 
testing must be conducted to demonstrate inhibition of microbial growth 
within the solid wound dressing during use. This testing must include:
    (1) Establishment of the Minimum Effective Concentration (MEC) of 
the antimicrobial in the context of the final solid wound dressing 
under worst-case conditions.
    (2) Identification of the period of effectiveness (i.e., maximum 
product use life) based on concentration of antimicrobial, leachability 
data, and performance under worst-case simulated use conditions.
    (3) For the tests conducted, evaluation with clinically relevant 
microbial species, including available strains of challenge organisms 
containing specific antimicrobial resistance mechanisms as part of 
worst-case scenario performance testing.
    (B) Evaluation and identification of any probable risks for 
probable contributions to the development and spread of antimicrobial 
resistance must be provided, and must include:
    (1) Identification of the antimicrobial, proposed mechanism(s) of 
action, and expected spectrum of activity; and
    (2) An AMR assessment for each antimicrobial component, including 
the following characterization elements based on literature review:
    (i) Known resistance mechanisms;
    (ii) Transmissibility of resistance mechanisms;
    (iii) List of resistant microbial species; and
    (iv) Potential for coselection (e.g., via coresistance or cross-
resistance) for medically important antimicrobial resistance 
mechanisms.
    (iii) If the solid wound dressing contains animal-derived 
material(s), data must include:
    (A) A risk management assessment for the inclusion of animal-
derived material(s) which considers any probable risk associated with 
the presence of the animal tissue in the final finished solid wound 
dressing (including pathogen and parasite infection and immunological 
reaction). The risk management assessment must describe how these risks 
are controlled and mitigated by:
    (1) Documentation of the processing methods, including methods of 
animal husbandry and tissue selection as well as methods for tissue 
handling, storage, transport, and quarantine, that mitigate the risk of 
parasites and pathogens.
    (2) Performance data which demonstrates the ability of the 
manufacturing and sterilization procedures to ensure the adequate 
removal (i.e., clearance or inactivation) of parasites and pathogens 
(including bacteria, mycoplasma, fungi, virus, and transmissible 
spongiform encephalopathy agents) from the final finished solid wound 
dressing.
    (B) If the device contains materials derived from a new animal 
species or from manufacturing processes which cause structural changes 
(i.e., denaturation, modification) to the animal protein, performance 
data (e.g., patch and prick testing, human repeat insult patch testing) 
must demonstrate that the device is not immunogenic.
    (iv) If the solid wound dressing contains a botanical extract, 
additional supporting data must include:
    (A) A risk management assessment for including the botanical 
extract in the solid wound dressing which considers any probable risk 
associated with the presence of the botanical extract in the final 
finished solid wound dressing.
    (B) The risk management assessment must describe how these risks 
are

[[Page 83798]]

controlled and mitigated by providing the following:
    (1) The chemical composition of the botanical extract, including 
the identity and quantification of the chemical constituents and 
impurities (e.g., elemental impurities, residual solvents and 
pesticides, microbial contaminants, adventitious toxins, and 
degradation products) and the lot-to-lot consistency of the botanical 
extract within the final finished solid wound dressing.
    (2) Documentation of the botanical extract function and activities 
after topical application. Such information must describe the purpose 
of the botanical extract in the solid wound dressing and how it is 
present in appropriate amounts to perform as intended under anticipated 
conditions of use, including expected worst-case conditions.
    (3) Identification of any probable risk to health from use of the 
botanical extract and how these risks were evaluated and are mitigated 
via the botanical concentration in the final product, duration of body 
contact, manufacturing and process controls, performance data, and 
labeling for the solid wound dressing.
    (v) The labeling must include:
    (A) A description of the intended user population;
    (B) Specific instructions regarding the proper placement, sizing, 
duration of use for the solid wound dressing, frequency of use, and 
removal of the solid wound dressing, if applicable;
    (C) A list of each ingredient or component within the solid wound 
dressing, including the functional role of that ingredient within the 
solid wound dressing;
    (D) A warning statement regarding any incompatibilities with other 
therapies;
    (E) A warning statement regarding the potential for the development 
of infection, including signs of an infection and a description of the 
steps to take in case of infection;
    (F) If the solid wound dressing is nonresorbable, a warning 
statement for the potential retention of material in the wound or the 
surrounding area;
    (G) A contraindication for any known sensitivity to components 
within the product;
    (H) A shelf life (i.e., maximum period the unopened solid wound 
dressing is stable while stored on the shelf under a specified range of 
environmental conditions);
    (I) A maximum use life per application of solid wound dressing 
(i.e., period the solid wound dressing is recommended for use prior to 
removal);
    (J) A statement regarding when to discontinue use of the solid 
wound dressing after multiple reapplications based on biocompatibility 
and performance testing; and
    (K) For solid wound dressings indicated for over-the-counter use, a 
statement specifying conditions, uses, or purposes for which the 
product may be safely administered by a lay user without the 
supervision of a licensed practitioner.
    (vi) If the solid wound dressing contains an antimicrobial, the 
labeling must also include:
    (A) Statement of the role of the antimicrobial in the product.
    (B) A warning statement regarding the potential for selection of 
antibiotic resistant organisms if the wound dressing contains an 
antimicrobial with a medium level of AMR concern.
    (C) Specific instructions regarding how and when to properly 
dispose of the product.
    (D) A statement of general effectiveness, such as 
``antimicrobial,'' ``antibacterial,'' or ``microbial barrier,'' without 
listing specific test organisms or log reduction values.
    (E) A statement explaining that the effectiveness of the 
antimicrobial in affecting wound bioburden has not been evaluated or 
established.
    (F) A warning statement regarding the potential for the 
antimicrobial to leach from the dressing and negatively impact the skin 
microbiota in the periwound area which may result in impaired wound 
healing.
    (vii) Any statements in the labeling must be clear such that they 
may be understood by the end user, supported by appropriate evidence, 
and consistent with the intended use of covering and protecting a 
wound, absorbing exudate, and maintaining appropriate moisture balance 
within the wound.
0
3. Add Sec.  878.4017 to subpart E to read as follows:


Sec.  878.4017  Wound dressings formulated as a gel, cream, or ointment 
containing antimicrobials and/or other chemicals.

    (a) Identification. A wound dressing formulated as a gel, cream, or 
ointment containing antimicrobials and/or other chemicals that are in a 
category listed in paragraph (a)(2) of this section is used to maintain 
appropriate moisture balance within the wound and is intended for use 
only on external cutaneous (skin) wounds. The wound dressing materials 
are synthetic or naturally derived materials (including animal-derived 
materials such as collagen or chitosan). Wound dressings formulated as 
a gel, cream, or ointment containing antimicrobials and/or other 
chemicals are amorphous and can have high water content with thickening 
agents or consist of an oil-water emulsion. This regulation does not 
include a wound dressing formulated as a gel, cream, or ointment that 
contains only animal-derived materials without the presence of 
antimicrobials and/or other chemicals.
    (1) Antimicrobials are used for preservative purposes only to 
maintain shelf life for a nonsterile wound dressing or a multiple-use 
wound dressing for single patient use only;
    (2) Categories of other chemicals are wound protectants, honey, 
synthetic peptides, or botanical extracts.
    (b) Classification. (1) Class III (premarket approval) for wound 
dressings formulated as a gel, cream, or ointment that are identified 
in paragraph (a) of this section and that contain one or more medically 
important antimicrobials acting as preservatives.
    (i) Date premarket approval application is required. A PMA is 
required to be filed with the Food and Drug Administration on or before 
[DATE OF THE LAST DAY OF THE 30TH FULL CALENDAR MONTH AFTER EFFECTIVE 
DATE OF FINAL RULE], for any wound dressing formulated as a gel, cream, 
or ointment, as identified in paragraph (a) of this section, that 
either contains one or more medically important antimicrobials acting 
as preservatives and was in commercial distribution before May 28, 
1976, or has, on or before [DATE OF THE LAST DAY OF THE 30TH FULL 
CALENDAR MONTH AFTER EFFECTIVE DATE OF FINAL RULE], been found to be 
substantially equivalent to any wound dressing formulated as a gel, 
cream, or ointment, as identified in paragraph (a) of this section, 
that contains one or more medically important antimicrobials and that 
was in commercial distribution before May 28, 1976. Any other wound 
dressing formulated as a gel, cream, or ointment, as identified in 
paragraph (a) of this section, that contains one or more medically 
important antimicrobials shall have an approved PMA in effect before 
being placed in commercial distribution.
    (ii) [Reserved]
    (2) Class II (special controls) for wound dressings formulated as a 
gel, cream, or ointment that are identified in paragraph (a) of this 
section and that contain one or more antimicrobials acting as 
preservatives with a medium or low level of AMR concern and/or other 
chemicals. The special controls are:

[[Page 83799]]

    (i) Performance testing and descriptive information. Performance 
testing and descriptive information must demonstrate the functionality 
of the wound dressing formulated as a gel, cream, or ointment to 
achieve the specified use, including:
    (A) The physical and chemical characteristics of the wound dressing 
formulated as a gel, cream, or ointment must be established. The 
following must be provided:
    (1) Identity, quantification, and purpose of each component in the 
finished product;
    (2) Specifications and characterization of each component in the 
finished product;
    (3) Demonstration that each component has a purpose and is present 
in appropriate amounts to perform as intended under anticipated 
conditions of use, including evaluation of expected worst-case 
conditions; and
    (4) Final release specifications for the manufactured wound 
dressing formulated as a gel, cream, or ointment.
    (B) If labeled as sterile, the wound dressing formulated as a gel, 
cream, or ointment must be demonstrated to be sterile and the 
sterilization process must be validated. If labeled as nonsterile, 
performance data must demonstrate that the product may not be 
sterilized by established sterilization methods and each manufactured 
lot of product has an acceptable bioburden level that is maintained 
throughout the stated shelf life.
    (C) The wound dressing formulated as a gel, cream, or ointment must 
be demonstrated to be biocompatible.
    (D) Bench performance testing data must demonstrate that the wound 
dressing formulated as a gel, cream, or ointment performs as intended 
under anticipated conditions of use, including evaluation of expected 
worst-case conditions.
    (E) Performance data must support the shelf life of the wound 
dressing formulated as a gel, cream, or ointment by demonstrating 
package integrity and product functionality over the identified shelf 
life. If the product is intended for multiple uses after opening, 
continued low bioburden, product stability, and functionality over the 
identified use life must be demonstrated.
    (ii) Antimicrobial characterization and preservative effectiveness 
testing. For wound dressings formulated as a gel, cream, or ointment 
containing antimicrobials with a medium or low level of AMR concern, 
antimicrobial characterization and preservative effectiveness testing 
must address the following:
    (A) Performance data must demonstrate that the antimicrobial has a 
purpose and is present in appropriate amounts to perform as intended 
under anticipated conditions of use and storage conditions, including 
evaluation of worst-case conditions. This testing must include:
    (1) Establishment of the MEC of the antimicrobial in the context of 
the final wound dressing formulated as a gel, cream, or ointment.
    (2) Identification of the period of preservative effectiveness for 
multiple-use products (i.e., after the product has been opened) based 
on concentration of antimicrobial and preservative effectiveness 
testing under worst-case simulated use conditions.
    (3) Preservative effectiveness testing must be conducted on at 
least three different manufactured lots of the final, finished device 
that has been real-time aged for the stated shelf life. If the dressing 
is a multiple-use product, the test articles should also be conditioned 
based on worst-case simulated use for maximum use life.
    (4) For nonsterile products, information should be provided 
regarding the characterization of bioburden within the product.
    (B) Evaluation and identification of any probable risks for 
probable contributions to the development and spread of antimicrobial 
resistance must be provided, and must include:
    (1) Identification of the antimicrobial, proposed mechanism(s) of 
action, and expected spectrum of activity; and
    (2) An AMR assessment for each antimicrobial component, including 
the following characterization elements based on literature review:
    (i) Known resistance mechanisms;
    (ii) Transmissibility of resistance mechanisms;
    (iii) List of resistant microbial species; and
    (iv) Potential for coselection (e.g., via coresistance or cross-
resistance) for medically important antimicrobial resistance 
mechanisms.
    (iii) If the wound dressing formulated as a gel, cream, or ointment 
contains animal-derived material(s), data must include:
    (A) A risk management assessment for the inclusion of animal-
derived material(s) which considers any probable risk associated with 
the presence of the animal tissue in the final finished wound dressing 
formulated as a gel, cream, or ointment (including pathogen and 
parasite infection and immunological reaction). The risk management 
assessment must describe how these risks are controlled and mitigated 
by:
    (1) Documentation of the processing methods, including animal 
husbandry and tissue selection as well as methods for tissue storage, 
transport, and quarantine, that mitigate the risk of parasites and 
pathogens.
    (2) Performance data which demonstrates the ability of the 
manufacturing and sterilization procedures to ensure the adequate 
removal (i.e., clearance or inactivation) of parasites and pathogens 
(including bacteria, mycoplasma, fungi, virus, and transmissible 
spongiform encephalopathy agents) from the final finished wound 
dressing formulated as a gel, cream, or ointment.
    (B) If the device contains materials derived from a new animal 
species or from manufacturing processes which cause structural changes 
(i.e., denaturation, modification) to the animal protein, performance 
data (e.g., patch and prick testing, human repeat insult patch testing) 
must demonstrate that the device is not immunogenic.
    (iv) If the wound dressing formulated as a gel, cream, or ointment 
contains a botanical extract, additional supporting data must include:
    (A) A risk management assessment for including the botanical 
extract in the wound dressing formulated as a gel, cream, or ointment 
which considers any probable risk associated with the presence of the 
botanical extract in the final finished wound dressing formulated as a 
gel, cream, or ointment.
    (B) The risk management assessment must describe how these risks 
are controlled and mitigated by providing the following:
    (1) The chemical composition of the botanical extract, including 
the identity and quantification of the chemical constituents and 
impurities (e.g., elemental impurities, residual solvents and 
pesticides, microbial contaminants, adventitious toxins, and 
degradation products), and the lot-to-lot consistency of the botanical 
extract within the final finished wound dressing formulated as a gel, 
cream, or ointment.
    (2) Documentation of the botanical extract function and activities 
after topical application. Such information must describe the purpose 
of the botanical extract in the wound dressing formulated as a gel, 
cream, or ointment and how it is present in appropriate amounts to 
perform as intended under anticipated conditions of use, including 
expected worst-case conditions.
    (3) Identification of any probable risk to health from use of the 
botanical extract and how these risks were evaluated and are mitigated 
via the botanical concentration in the final product, duration of body 
contact,

[[Page 83800]]

manufacturing and process controls, performance data, and labeling for 
the wound dressing formulated as a gel, cream, or ointment.
    (v) The labeling must include:
    (A) A description of the intended user population;
    (B) Specific instructions regarding the proper application of the 
product, duration of use for the wound dressing, frequency of use, and 
instructions regarding the removal of the product residuals prior to 
reapplication, if applicable;
    (C) A list of each ingredient or component within the wound 
dressing, including the functional role of that ingredient within the 
wound dressing;
    (D) A warning statement regarding any incompatibilities with other 
therapies;
    (E) A warning statement regarding the potential for the development 
of infection, including signs of an infection and a description of the 
steps to take in case of infection;
    (F) A contraindication for any known sensitivity to components 
within the product;
    (G) A shelf life (i.e., maximum period the unopened wound dressing 
formulated as a gel, cream, or ointment is stable while stored on the 
shelf under a specified range of environmental conditions);
    (H) The maximum period of use (including reapplications) based on 
biocompatibility and performance testing; and
    (I) For wound dressings formulated as a gel, cream, or ointment 
indicated for over-the-counter use, a statement specifying conditions, 
uses, or purposes for which the product may be safely administered by a 
lay user without the supervision of a licensed practitioner.
    (vi) If the wound dressing formulated as a gel, cream, or ointment 
contains an antimicrobial, the labeling must also include:
    (A) Statement of the role of the antimicrobial in the product.
    (B) A warning statement regarding the potential for selection of 
antibiotic resistant organisms if the wound dressing contains an 
antimicrobial with a medium level of AMR concern.
    (C) Specific instructions regarding how and when to properly 
dispose of the product.
    (D) A statement of general effectiveness, such as 
``antimicrobial,'' ``antibacterial,'' or ``microbial barrier,'' without 
listing specific test organisms or log reduction values.
    (E) A statement explaining that the effectiveness of the 
antimicrobial in affecting wound bioburden has not been evaluated or 
established.
    (F) A warning statement regarding the potential for the 
antimicrobial to leach from the dressing and negatively impact the skin 
microbiota in the periwound area which may result in impaired wound 
healing.
    (vii) Any statements in the labeling must be clear such that they 
may be understood by the end user, supported by appropriate evidence, 
and consistent with the intended use of maintaining appropriate 
moisture balance within the wound.
0
4. Add Sec.  878.4019 to subpart E to read as follows:


Sec.  878.4019  Liquid wound washes.

    (a) Identification. A liquid wound wash containing antimicrobials 
and/or other chemicals that are in a category listed in paragraph 
(a)(2) of this section is a water-based solution used to mechanically 
irrigate and physically remove debris from external wounds and intended 
for use on external cutaneous (skin) wounds. It is also used to moisten 
solid wound dressings to maintain appropriate moisture balance within 
the dressing. This regulation does not include liquid wound washes that 
contain only animal-derived materials without the presence of 
antimicrobials and/or other chemicals.
    (1) Antimicrobials are used for preservative purposes only to 
maintain shelf life for a nonsterile liquid wound wash or a multiple-
use liquid wound wash for single patient use only;
    (2) Categories of other chemicals are wound protectants, honey, 
synthetic peptides, or botanical extracts.
    (b) Classification. (1) Class III (premarket approval) for liquid 
wound washes that are identified in paragraph (a) of this section and 
that contain one or more medically important antimicrobials acting as 
preservatives.
    (i) Date premarket approval application is required. A PMA is 
required to be filed with the Food and Drug Administration on or before 
[DATE OF THE LAST DAY OF THE 30TH FULL CALENDAR MONTH AFTER EFFECTIVE 
DATE OF FINAL RULE], for any liquid wound wash, as identified in 
paragraph (a) of this section, that either contains one or more 
medically important antimicrobials and was in commercial distribution 
before May 28, 1976, or has, on or before [DATE OF THE LAST DAY OF THE 
30TH FULL CALENDAR MONTH AFTER EFFECTIVE DATE OF FINAL RULE], been 
found to be substantially equivalent to any liquid wound wash, as 
identified in paragraph (a) of this section, that contains one or more 
medically important antimicrobials and that was in commercial 
distribution before May 28, 1976. Any other liquid wound wash, as 
identified in paragraph (a) of this section, that contains one or more 
medically important antimicrobials shall have an approved PMA in effect 
before being placed in commercial distribution.
    (ii) [Reserved]
    (2) Class II (special controls) for liquid wound washes that are 
identified in paragraph (a) of this section and that contain one or 
more antimicrobials acting as preservatives with a medium or low level 
of AMR concern and/or other chemicals or when containing water or 0.9 
percent saline only. The special controls for this device are:
    (i) Performance testing and descriptive information. Performance 
testing and descriptive information must demonstrate the functionality 
of the liquid wound wash to achieve the specified use, including:
    (A) The physical and chemical characteristics of the liquid wound 
wash must be established. The following must be provided:
    (1) Identity, quantification, and purpose of each component in the 
finished product;
    (2) Specifications and characterization of each component in the 
finished product;
    (3) Demonstration that each component has a purpose and is present 
in appropriate amounts to perform as intended under anticipated 
conditions of use, including evaluation of expected worst-case 
conditions; and
    (4) Final release specifications for the manufactured liquid wound 
wash.
    (B) If labeled as sterile, the liquid wound wash must be 
demonstrated to be sterile and the sterilization process must be 
validated. If labeled as nonsterile, performance data must demonstrate 
that the product may not be sterilized by established sterilization 
methods and each manufactured lot of product has an acceptable 
bioburden level that is maintained throughout the stated shelf life.
    (C) The liquid wound wash must be demonstrated to be biocompatible.
    (D) Bench performance testing data must demonstrate that the liquid 
wound wash performs as intended under anticipated conditions of use, 
including evaluation of expected worst-case conditions.
    (F) Performance data must support the shelf life of the liquid 
wound wash by demonstrating package integrity and product functionality 
over the identified shelf life. If the product is intended for multiple 
uses after opening, continued low bioburden, product stability, and 
functionality over the identified use life must be demonstrated.

[[Page 83801]]

    (ii) Antimicrobial characterization and preservative effectiveness 
testing. For liquid wound washes containing antimicrobials with a 
medium or low level of AMR concern, antimicrobial characterization and 
preservative effectiveness testing must address the following:
    (A) Performance data must demonstrate that the antimicrobial has a 
purpose and is present in appropriate amounts to perform as intended 
under anticipated conditions of use and storage conditions, including 
evaluation of worst-case conditions. This testing must include:
    (1) Establishment of the MEC of the antimicrobial in the context of 
the final liquid wound wash.
    (2) Identification of the period of preservative effectiveness for 
multiple-use products (i.e., after the product has been opened) based 
on concentration of antimicrobial and preservative effectiveness 
testing under worst-case simulated use conditions.
    (3) Preservative effectiveness testing must be conducted on at 
least three different manufactured lots of the final, finished device 
that has been real-time aged for the stated shelf life. If the liquid 
wound wash is a multiple-use product, the test articles should also be 
conditioned based on worst-case simulated use for maximum use life.
    (4) For nonsterile products, information should be provided 
regarding the characterization of bioburden within the product.
    (B) Evaluation and identification of any probable risks for 
probable contributions to the development and spread of antimicrobial 
resistance must be provided, and must include:
    (1) Identification of the antimicrobial, proposed mechanism(s) of 
action, and expected spectrum of activity; and
    (2) An AMR assessment for each antimicrobial component, including 
the following characterization elements based on literature review:
    (i) Known resistance mechanisms;
    (ii) Transmissibility of resistance mechanisms;
    (iii) List of resistant microbial species; and
    (iv) Potential for coselection (e.g., via coresistance or cross-
resistance) for medically important antimicrobial resistance 
mechanisms.
    (iii) If the liquid wound wash contains animal-derived material(s), 
data must include:
    (A) A risk management assessment for the inclusion of animal-
derived material(s) which considers any probable risk associated with 
the presence of the animal tissue in the final finished liquid wound 
wash (including pathogen and parasite infection and immunological 
reaction). The risk management assessment must describe how these risks 
are controlled and mitigated by:
    (1) Documentation of the processing methods, including animal 
husbandry and tissue selection as well as methods for tissue storage, 
transport, and quarantine, that mitigate the risk of parasites and 
pathogens.
    (2) Performance data which demonstrates the ability of the 
manufacturing and sterilization procedures to ensure the adequate 
removal (i.e., clearance or inactivation) of parasites and pathogens 
(including bacteria, mycoplasma, fungi, virus, and transmissible 
spongiform encephalopathy agents) from the final finished liquid wound 
wash.
    (B) If the device contains materials derived from a new animal 
species or from manufacturing processes which cause structural changes 
(i.e., denaturation, modification) to the animal protein, performance 
data (e.g., patch and prick testing, human repeat insult patch testing) 
must demonstrate that the device is not immunogenic.
    (iv) If the liquid wound wash contains a botanical extract, 
additional supporting data must include:
    (A) A risk management assessment for including the botanical 
extract in the liquid wound wash which considers any probable risk 
associated with the presence of the botanical extract in the final 
finished liquid wound wash.
    (B) The risk management assessment must describe how these risks 
are controlled and mitigated by providing the following:
    (1) The chemical composition of the botanical extract, including 
the identity and quantification of the chemical constituents and 
impurities (e.g., elemental impurities, residual solvents and 
pesticides, microbial contaminants, adventitious toxins, and 
degradation products), and the lot-to-lot consistency of the botanical 
extract within the final finished liquid wound wash.
    (2) Documentation of the botanical extract function and activities 
after topical application. Such information must describe the purpose 
of the botanical extract in the liquid wound wash and how it is present 
in appropriate amounts to perform as intended under anticipated 
conditions of use, including expected worst-case conditions.
    (3) Identification of any probable risk to health from use of the 
botanical extract and how these risks were evaluated and are mitigated 
via the botanical concentration in the final product, duration of body 
contact, manufacturing and process controls, performance data, and 
labeling for the liquid wound wash.
    (v) The labeling must include:
    (A) A description of the intended user population;
    (B) Specific instructions regarding the proper application of the 
product, duration of use for the liquid wound wash, and frequency of 
use if labeled for a period of multiple use;
    (C) A list of each ingredient or component within the liquid wound 
wash, including the functional role of that ingredient within the 
liquid wound wash;
    (D) A warning statement regarding any incompatibilities with other 
therapies;
    (E) A warning statement regarding the potential for the development 
of infection, including signs of an infection and a description of the 
steps to take in case of infection;
    (F) A contraindication for any known sensitivity to components 
within the product;
    (G) A shelf life (i.e., maximum period the unopened liquid wound 
wash is stable while stored on the shelf under a specified range of 
environmental conditions);
    (H) A maximum period of use (including reapplications) based on 
biocompatibility and performance testing.
    (I) For liquid wound washes indicated for over-the-counter use, a 
statement specifying conditions, uses, or purposes for which the 
product may be safely administered by a lay user without the 
supervision of a licensed practitioner.
    (vi) If the liquid wound wash contains an antimicrobial, the 
labeling must also include:
    (A) Statement of the role of the antimicrobial in the product as a 
preservative.
    (B) A warning statement regarding the potential for selection of 
antibiotic resistant organisms if the liquid wound wash contains an 
antimicrobial with a medium level of AMR concern.
    (C) Specific instructions regarding how and when to properly 
dispose of the product.
    (D) A statement of general effectiveness, such as 
``antimicrobial,'' ``antibacterial,'' or ``microbial barrier,'' without 
listing specific test organisms or log reduction values.
    (E) A statement explaining that the effectiveness of the 
antimicrobial in affecting wound bioburden has not been evaluated or 
established.
    (F) A warning statement regarding the potential for the 
antimicrobial to leach from the dressing and negatively impact the skin 
microbiota in the periwound

[[Page 83802]]

area which may result in impaired wound healing.
    (vii) Any statements in the labeling must be clear such that they 
may be understood by the end user, supported by appropriate evidence, 
and consistent with the intended use of mechanically irrigating a wound 
or maintaining appropriate moisture balance within a solid wound 
dressing.

    Dated: November 21, 2023.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2023-26209 Filed 11-29-23; 8:45 am]
 BILLING CODE 4164-01-P