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Proposed Rule2023-26209

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

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Published

November 30, 2023

Issuing agencies

Health and Human Services DepartmentFood and Drug Administration

Abstract

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).

Full Text

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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, <a href="/cdn-cgi/l/email-protection#d8baaab9b6bcb7b6f6b3b1acbbb0bdb498bebcb9f6b0b0abf6bfb7ae">[email&#160;protected]</a>.

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

[[Page 83775]]

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: <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff</a>.
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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 <a href="https://www.fda.gov/media/80384/download">https://www.fda.gov/media/80384/download</a>.
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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 (<a href="https://www.who.int/publications/i/item/9789241515528">https://www.who.int/publications/i/item/9789241515528</a>). 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 (<a href="https://www.fda.gov/media/172347/download?attachment">https://www.fda.gov/media/172347/download?attachment</a>), 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

[[Page 83776]]

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

[[Page 83777]]

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

------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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\
---------------------------------------------------------------------------

\13\ FDA Premarket Approval, Integra Omnigraft Dermal
Regeneration Matrix, <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P900033S042">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P900033S042</a>.
\14\ Drugs at FDA, Silver Sulfadiazine Cream, <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017381s053lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017381s053lbl.pdf</a>.
\15\ FDA Premarket Approval, OrCel\TM\ (Bilayered Cellular
Matrix), <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010016">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010016</a>.
---------------------------------------------------------------------------

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:
<bullet> 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.
<bullet> 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 <a href="https://www.cell.com/trends/microbiology/fulltext/S0966-842X">https://www.cell.com/trends/microbiology/fulltext/S0966-842X</a>(06)00051-5.
---------------------------------------------------------------------------

<bullet> 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.
<bullet> 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 <a href="https://dps.fda.gov/omuf">https://dps.fda.gov/omuf</a>. 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.

---------------------------------------------------------------------------

[[Page 83780]]

<bullet> Honey. Wound dressings may contain honey, which helps
maintain moisture balance within the dressing.
<bullet> Synthetic Peptides. Wound dressings may include synthetic
peptides, which are used to create a fibrous scaffold and provide
physical structure to the wound dressing.
<bullet> 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

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 <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm</a>.
---------------------------------------------------------------------------

<bullet> 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.
<bullet> 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 <a href="https://www.govinfo.gov/content/pkg/FR-2022-10-06/pdf/2022-21746.pdf">https://www.govinfo.gov/content/pkg/FR-2022-10-06/pdf/2022-21746.pdf</a>. 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.
---------------------------------------------------------------------------

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

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

<bullet> 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.
---------------------------------------------------------------------------

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

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

<bullet> Dressings with hydrocortisone.26
---------------------------------------------------------------------------

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

<bullet> 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:
<bullet> Nonresorbable gauze/sponge for external use at Sec.
878.4014 (Product Codes: MAC, OVR, LZM, NAB, OHO, PKD, PXY, PYJ, PYK,
PYL);
<bullet> Hydrophilic wound dressing at Sec. 878.4018 (Product
Codes: KOZ, MGO, NAC);
<bullet> Occlusive wound dressing at Sec. 878.4020 (Product Code:
NAD);
<bullet> Hydrogel wound dressing and burn dressing at Sec.
878.4022 (Product Codes: NAE, OJJ, PXQ);
<bullet> 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:
<bullet> 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.
<bullet> 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.
<bullet> 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:
<bullet> 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.
<bullet> 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'' (<a href="https://www.fda.gov/media/80384/download">https://www.fda.gov/media/80384/download</a>).
---------------------------------------------------------------------------

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:
<bullet> 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).
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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\
---------------------------------------------------------------------------

\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.
<bullet> 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.
<bullet> 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).
<bullet> 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.
<bullet> 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.
---------------------------------------------------------------------------

\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:
<bullet> 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.
<bullet> 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.
<bullet> 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:
<bullet> 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.
<bullet> Immunological reaction: This can result from a device
derived from a new animal source or protein denaturation/modification
due to the manufacturing conditions.
<bullet> 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.
<bullet> 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.
<bullet> Delayed wound healing: Cytotoxicity resulting in dead or
necrotic tissue can delay healing.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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:
<bullet> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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................ <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Immunological reaction................. <bullet> Performance testing
and descriptive information.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Transmission of pathogens and parasites <bullet> Performance testing
(e.g., bacteria, mycoplasma, fungi, and descriptive information.
viruses, and other transmissible <bullet> Risk management
spongiform encephalopathy agents). assessment for the inclusion
of animal-derived material.
<bullet> Labeling.
Toxicity............................... <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Delayed wound healing.................. <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Labeling.
Incompatibilities with other therapies. <bullet> Labeling.

[[Page 83791]]

Contribution to the spread of <bullet> Antimicrobial
antimicrobial resistance (AMR). Characterization and
Performance Testing.
<bullet> AMR risk assessment.
<bullet> Labeling.
Infection.............................. <bullet> Antimicrobial
Characterization and
Performance Testing.
<bullet> Shelf life validation.
<bullet> Sterilization
validation.
<bullet> Risk management
assessment for animal-derived
materials and/or botanical
extracts.
<bullet> Labeling.
Microbial growth within the product <bullet> Antimicrobial
during use. Characterization and
Performance Testing.
<bullet> Sterilization
validation.
Product degradation during stated shelf <bullet> Shelf life validation.
storage. <bullet> Labeling.
Retention of dressing material in wound <bullet> Performance testing
and descriptive information.
<bullet> Labeling.
Loss of Barrier function............... <bullet> Antimicrobial
Characterization and
Performance Testing.
Negatively impacting the skin <bullet> Antimicrobial
microbiota in the periwound area Characterization and
resulting in impaired wound healing. Performance Testing.
<bullet> 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................ <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Immunological reaction................. <bullet> Performance testing
and descriptive information.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Transmission of pathogens and parasites <bullet> Performance testing
(e.g., bacteria, mycoplasma, fungi, and descriptive information.
viruses, and other transmissible <bullet> Risk management
spongiform encephalopathy agents). assessment for the inclusion
of animal-derived material.
<bullet> Labeling.
Toxicity............................... <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Delayed wound healing.................. <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Labeling.
Incompatibilities with other therapies. <bullet> Labeling.
Contribution to the spread of <bullet> Antimicrobial
antimicrobial resistance (AMR). Characterization and
Preservative Effectiveness
Testing.
<bullet> AMR risk assessment.
<bullet> Labeling.
Infection.............................. <bullet> Antimicrobial
Characterization and
Preservative Effectiveness
Testing.
<bullet> Shelf life validation.
<bullet> Sterilization
validation.
<bullet> Risk management
assessment for animal-derived
materials and/or botanical
extracts.
<bullet> Labeling.
Microbial growth within the product <bullet> Antimicrobial
during storage. Characterization and
Preservative Effectiveness
Testing.
<bullet> Sterilization
validation.
Product degradation during stated shelf <bullet> Shelf life validation.
storage. <bullet> Labeling.
Negatively impacting the skin <bullet> Antimicrobial
microbiota in the periwound area Characterization and
resulting in impaired wound healing. Performance Testing.
<bullet> 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................ <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Immunological reaction................. <bullet> Performance testing
and descriptive information.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Transmission of pathogens and parasites <bullet> Performance testing
(e.g., bacteria, mycoplasma, fungi, and descriptive information.
viruses, and other transmissible <bullet> Risk management
spongiform encephalopathy agents). assessment for the inclusion
of animal-derived material.
<bullet> Labeling.
Toxicity............................... <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Risk management
assessment for the inclusion
of animal-derived material and/
or botanical extracts.
<bullet> Labeling.
Delayed wound healing.................. <bullet> Performance testing
and descriptive information.
<bullet> Biocompatibility
evaluation.
<bullet> Labeling.
Incompatibilities with other therapies. <bullet> Labeling.
Contribution to the spread of <bullet> Antimicrobial
antimicrobial resistance (AMR). Characterization and
Preservative Effectiveness
Testing.
<bullet> AMR risk assessment.
<bullet> Labeling.
Infection.............................. <bullet> Antimicrobial
Characterization and
Preservative Effectiveness
Testing.
<bullet> Shelf life validation.
<bullet> Sterilization
validation.
<bullet> Risk management
assessment for animal-derived
materials and/or botanical
extracts.
<bullet> Labeling.
Microbial growth within the product <bullet> Antimicrobial
during storage. Characterization and
Preservative Effectiveness
Testing.
<bullet> Sterilization
validation.
Product degradation during stated shelf <bullet> Shelf life validation.
storage.
<bullet> Labeling.
Inability to remove wound debris and <bullet> Performance testing
foreign materials. and descriptive information.
<bullet> Labeling.
Negatively impacting the skin <bullet> Antimicrobial
microbiota in the periwound area Characterization and
resulting in impaired wound healing. Performance Testing.
<bullet> 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

<bullet> 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.
<bullet> 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 <a href="https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria">https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria</a>.

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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without
asterisks are not on public display at <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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.

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2019. Available at <a href="https://pubmed.ncbi.nlm.nih.gov/30849351/">https://pubmed.ncbi.nlm.nih.gov/30849351/</a>.
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 <a href="https://pubmed.ncbi.nlm.nih.gov/30528317/">https://pubmed.ncbi.nlm.nih.gov/30528317/</a>.
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 <a href="https://pubmed.ncbi.nlm.nih.gov/35148643/">https://pubmed.ncbi.nlm.nih.gov/35148643/</a>.
47. Saad A., E. Salazar, L. Allen, et al., ``Antimicrobial Dressing
Versus Standard Dressing in Obese Women Undergoing Cesarean
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Perinatology, 39(9), 951-958, 2022. Available at <a href="https://pubmed.ncbi.nlm.nih.gov/33264808/">https://pubmed.ncbi.nlm.nih.gov/33264808/</a>.
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,
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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 <a href="https://pubmed.ncbi.nlm.nih.gov/29358051/">https://pubmed.ncbi.nlm.nih.gov/29358051/</a>.
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 <a href="https://doi.org/10.3390/ijms19092699">https://doi.org/10.3390/ijms19092699</a>.
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 <a href="https://doi.org/10.1111/jcmm.14415">https://doi.org/10.1111/jcmm.14415</a>.
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 <a href="https://doi.org/10.3389/fimmu.2020.550946">https://doi.org/10.3389/fimmu.2020.550946</a>.
53. Luqman A., M. Muttaqin, S. Yulaipi, et al., ``Trace Amines
Produced by Skin Bacteria Accelerate Wound Healing in Mice,''
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54. Brown M., A. Horswill, ``Staphylococcus Epidermidis--Skin Friend
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*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 <a href="https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria">https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria</a>.

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
t

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