Antiseptic Rub FDA Final Rule Making

Federal Register / Vol. 84, No.
71 / Friday, April 12, 2019 / Rules and Regulations 14847
(A) Drain the engine oil and disconnect the information on the availability of this published in the Federal Register of
F723–1 line assembly from the tank fitting at material at the FAA, call (817) 222–5110. June 17, 1994 (the 1994 TFM), as
the firewall, using as reference Figure 1 of (5) You may view this service information amended by the proposed rule
Robinson Helicopter Company R66 Service that is incorporated by reference at the
published in the Federal Register (FR)
Bulletin SB–21A, Revision A, dated June 6, National Archives and Records
Administration (NARA). For information on of June 30, 2016 (2016 Consumer
2017.
(B) Pinch the flanges of G805–1 angle at the the availability of this material at NARA, call Antiseptic Rub proposed rule).
minimum required to enable insertion, and (202) 741–6030, or go to: http:// DATES: Effective April 13, 2020.
insert the angle in the oil tank outlet fitting www.archives.gov/federal-register/cfr/ibr-
until the angle snaps in place. locations.html. ADDRESSES: For access to the docket to
(C) Connect the F723–1 line assembly to Issued in Fort Worth, Texas, on March 26, read background documents or
the tank fitting. Special torque nut to 675 in.- 2019. comments received, go to https://
lb. Torque stripe the fitting. www.regulations.gov and insert the
Lance T. Gant,
(ii) If the identification ink stamp is docket number found in brackets in the
followed by a revision letter J, determine if Director, Compliance & Airworthiness
Division, Aircraft Certification Service. heading of this final rule, into the
there is a yellow dot near the ink stamp. A
yellow dot indicates that the angle has been [FR Doc. 2019–07177 Filed 4–11–19; 8:45 am] ‘‘Search’’ box and follow the prompts,
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angle by following the procedures in
paragraphs (e)(2)(i)(A) through (e)(2)(i)(C) of DEPARTMENT OF HEALTH AND FOR FURTHER INFORMATION CONTACT:
this AD. HUMAN SERVICES Anita Kumar, Center for Drug
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21 CFR Part 310 Silver Spring, MD 20993–0002, 301–
(f) Alternative Methods of Compliance
(AMOCs) [Docket No. FDA–2016–N–0124 (formerly 796–1032.
(1) The Manager, Los Angeles ACO Branch, part of Docket No. FDA–1975–N–0012)]
SUPPLEMENTARY INFORMATION:
FAA, may approve AMOCs for this AD. Send RIN 0910–AH97
your proposal to: Danny Nguyen, Aerospace Table of Contents
Engineer, Los Angeles ACO Branch, Safety and Effectiveness of Consumer I. Executive Summary
Compliance and Airworthiness Division, Antiseptic Rubs; Topical Antimicrobial A. Purpose of the Final Rule
FAA, 3960 Paramount Blvd., Lakewood,
Drug Products for Over-the-Counter B. Summary of the Major Provisions of the
California 90712; telephone (562) 627–5247;
email 9-ANM-LAACO-AMOC-REQUESTS@ Human Use Final Rule
C. Costs and Benefits
faa.gov. AGENCY: Food and Drug Administration,
(2) For operations conducted under a 14 II. Table of Abbreviations/Commonly Used
HHS. Acronyms in This Document
CFR part 119 operating certificate or under
14 CFR part 91, subpart K, we suggest that ACTION: Final rule; finding of III. Introduction
you notify your principal inspector, or ineligibility for inclusion in final A. Terminology Used in the OTC Drug
lacking a principal inspector, the manager of monograph. Review Regulations
the local flight standards district office or B. Topical Antiseptics and Scope of
certificate holding district office before SUMMARY: The Food and Drug Document
operating any aircraft complying with this Administration (FDA, the Agency, or IV. Background
AD through an AMOC. we) is issuing this final action A. Significant Rulemakings Relevant to
establishing that certain active This Document
(g) Subject B. Public Meetings Relevant to This
ingredients used in nonprescription
Joint Aircraft Service Component (JASC) (also known as over-the-counter (OTC)) Document
Code: 7910, Engine Oil Storage (Airframe C. Eligibility for the OTC Drug Review
consumer antiseptic products intended
Furnished). D. Updated Statistical Analysis for Efficacy
for use without water (referred to
(h) Material Incorporated by Reference V. Comments on the Proposed Rule and FDA
throughout as consumer antiseptic rubs
Response
(1) The Director of the Federal Register or consumer rubs) are not eligible for A. Introduction
approved the incorporation by reference of evaluation under the OTC Drug Review B. General Comments on the Proposed
the service information listed in this for use in consumer antiseptic rubs. Rule and FDA Response
paragraph under 5 U.S.C. 552(a) and 1 CFR Drug products containing these C. Comments on Effectiveness and FDA
part 51. ineligible active ingredients will require Response
(2) You must use this service information
approval under a new drug application D. Comments on Safety and FDA Response
as applicable to do the actions required by
this AD, unless the AD specifies otherwise. (NDA) or abbreviated new drug E. Comments on the Preliminary
(i) Robinson Helicopter Company R66 application (ANDA) prior to marketing. Regulatory Impact Analysis and FDA
Service Bulletin SB–21A, Revision A, dated FDA is issuing this final action after Response
June 6, 2017. considering the recommendations of the VI. Effective Date
(ii) [Reserved] Nonprescription Drugs Advisory VII. Economic Analysis of Impacts
(3) For Robinson Helicopter Company Committee (NDAC), public comments A. Introduction
service information identified in this AD, B. Summary of Costs and Benefits
on the Agency’s notices of proposed
contact Robinson Helicopter Company, 2901 C. Summary of Regulatory Flexibility
rulemaking, and all data and Analysis
Airport Drive, Torrance, CA 90505; telephone
information on OTC consumer
jbell on DSK30RV082PROD with RULES
(310) 539–0508; fax (310) 539–5198; or at VIII. Paperwork Reduction Act of 1995
http://www.robinsonheli.com/servelib.htm. antiseptic rub products that have come IX. Analysis of Environmental Impact
(4) You may view this service information to the Agency’s attention. This final X. Consultation and Coordination With
at FAA, Office of the Regional Counsel, action finalizes the 1994 tentative final Indian Tribal Governments
Southwest Region, 10101 Hillwood Pkwy., monograph (TFM) for OTC consumer XI. Federalism
Room 6N–321, Fort Worth, TX 76177. For antiseptic rub drug products that XII. References
VerDate Sep<11>2014 16:08 Apr 11, 2019 Jkt 247001 PO 00000 Frm 00003 Fmt 4700 Sfmt 4700 E:\FR\FM\12APR1.SGM 12APR1
14848 Federal Register / Vol. 84, No. 71 / Friday, April 12, 2019 / Rules and Regulations
I. Executive Summary rule, we have not received any new rulemaking on these three ingredients
information since the publication of the (see Docket No. FDA–2016–N–0124 at
A. Purpose of the Final Rule
2016 Consumer Antiseptic Rub https://www.regulations.gov and also
This document finalizes the 2016 proposed rule demonstrating that the https://www.fda.gov/Drugs/DrugSafety/
Consumer Antiseptic Rub proposed active ingredients we previously InformationbyDrugClass/
rule. This final rule applies to active proposed to be ineligible should be ucm538131.htm).
ingredients used in consumer antiseptic considered eligible for evaluation under
rub products that are sometimes referred C. Costs and Benefits
the OTC Drug Review for inclusion in
to as rubs, leave-on products, or hand the OTC consumer antiseptic rub This document defers regulatory
‘‘sanitizers,’’ as well as to consumer monograph. Accordingly, consumer action for three consumer antiseptic rub
antiseptic wipes. These products are antiseptic rub drug products containing active ingredients (ethyl alcohol,
intended to be used when soap and any of these ineligible active ingredients isopropyl alcohol, and benzalkonium
water are not available and are left on require approval under an NDA or chloride) that are eligible for evaluation
and not rinsed off with water. We will ANDA prior to marketing. under the OTC Drug Review for use in
refer to them here as consumer This document covers only OTC OTC consumer antiseptic rub products,
antiseptic rubs or consumer rubs. consumer antiseptic rubs that are while establishing that all other
In response to several requests intended for use without water. This consumer rub active ingredients are
submitted to the 2016 Consumer document does not cover consumer ineligible for evaluation under the OTC
Antiseptic Rub proposed rule, FDA has antiseptic washes (78 FR 76444, 81 FR Drug Review and OTC consumer
deferred further rulemaking on three 61106); healthcare antiseptics (80 FR antiseptic rubs containing these
active ingredients used in OTC 25166, 82 FR 60474); antiseptics ineligible active ingredients require
consumer antiseptic rub products to identified as ‘‘first aid antiseptics’’ in approval under an NDA or ANDA prior
allow for the development and the 1991 First Aid tentative final to marketing. The costs of this
submission to the record of new safety monograph (TFM) (56 FR 33644); or document are associated with the
and effectiveness data for these antiseptics used by the food industry. reformulation and relabeling of
ingredients. The deferred active consumer rub products that currently
ingredients are benzalkonium chloride, B. Summary of the Major Provisions of
the Final Rule contain ineligible active ingredients.
alcohol (also referred to as ethanol or The benefits of this document include
ethyl alcohol), and isopropyl alcohol. This document finalizes the consumers’ reduced exposure to
Accordingly, FDA does not make a ineligibility status of the 28 active potentially unsafe consumer antiseptic
generally recognized as safe and ingredients listed in section IV.C.2. No rub products, as well as avoiding the
effective (GRAS/GRAE) determination additional information was submitted deadweight loss associated with
in this document for these three active demonstrating that any of the 28 reduced consumption of ineffective
ingredients for use in OTC consumer ineligible active ingredients identified products. FDA is only able to monetize
antiseptic rubs. The monograph or non- in the 2016 Consumer Antiseptic Rub the costs of this document. We estimate
monograph status of these three proposed rule are eligible for evaluation that the present value of the one-time
ingredients will be addressed, either under the OTC Drug Review for use in costs associated with compliance range
after completion and analysis of studies an OTC consumer antiseptic rub, and from $1.07 million to $2.50 million with
to address the safety and effectiveness thus, these ineligible ingredients are not a primary estimate of $1.87 million.
data gaps of these ingredients or at included in the OTC Consumer Annualizing upfront costs over a 10-
another time, if these studies are not Antiseptic Rub monograph at this time. year period at a discount rate of 3
completed. As discussed below, this OTC consumer antiseptic rub products percent, the costs of this document are
document describes the studies containing these ineligible ingredients estimated to be between $0.13 million
necessary as a scientific matter for the are new drugs for which approved and $0.29 million per year; the
Agency to determine whether an active NDAs or ANDAs are required prior to corresponding estimated cost at a
ingredient is GRAS/GRAE for use in marketing. discount rate of 7 percent is between
consumer rubs. Requests were made that $0.15 million and $0.36 million per
The three deferred active benzalkonium chloride, ethyl alcohol, year.
ingredients—benzalkonium chloride, and isopropyl alcohol be deferred from
The full discussion of economic
ethyl alcohol, and isopropyl alcohol— consideration in this consumer
impacts is available in Docket No. FDA–
are the only active ingredients antiseptic rub document to allow more
2016–N–0124 and at https://
determined to be eligible for evaluation time for interested parties to complete
www.fda.gov/AboutFDA/Reports
under the OTC Drug Review for use in necessary studies to fill the safety and
ManualsForms/Reports/
OTC consumer antiseptic rub products. effectiveness data gaps identified in the
EconomicAnalyses/default.htm.
With respect to the 28 ineligible active 2016 Consumer Antiseptic Rub
ingredients identified in the 2016 proposed rule for these ingredients. In II. Table of Abbreviations/Commonly
Consumer Antiseptic Rub proposed October 2017, we agreed to defer Used Acronyms in This Document
Abbreviation What it means
ANDA .................................. Abbreviated New Drug Application.

ANPR .................................. Advanced Notice of Proposed Rulemaking.
ASTM .................................. American Society for Testing and Materials International.
ATCC .................................. American Type Culture Collection.

ATE ..................................... Average Treatment Effect.
CFR .................................... Code of Federal Regulations.
FDA .................................... Food and Drug Administration.
FD&C Act ........................... Federal Food, Drug, and Cosmetic Act.
FR ....................................... Federal Register.
Federal Register / Vol. 84, No. 71 / Friday, April 12, 2019 / Rules and Regulations 14849
Abbreviation What it means
GRAS/GRAE ...................... Generally Recognized as Safe/Generally Recognized as Effective.

MBC .................................... Minimum Bactericidal Concentration.
MIC ..................................... Minimum Inhibitory Concentration.
MUsT .................................. Maximal Usage Trial.
NDA .................................... New Drug Application.
NDAC ................................. Nonprescription Drugs Advisory Committee.
OTC .................................... Over-the-counter.
PBPK .................................. Physiologically based pharmacokinetic.
PK ....................................... Pharmacokinetic.
RIA ...................................... Regulatory Impact Analysis.
TFM .................................... Tentative Final Monograph.
U.S.C .................................. United States Code.
III. Introduction the results of that testing or any other healthcare personnel hand wash; (3)
In the following sections, we provide data, must be done during the OTC drug patient preoperative skin preparation;
a brief description of terminology used rulemaking process before the and (4) surgical hand scrub (59 FR
in the OTC Drug Review regulations, an establishment of a final monograph (i.e., 31402 at 31442). In the 1994 TFM, FDA
overview of OTC topical antiseptic drug a final rule or regulation). Therefore, the also identified a new category of
products, and a more detailed proposed rules (at the tentative final antiseptics for use by the food industry
description of the OTC consumer monograph stage) used the concepts of and requested relevant data and
antiseptic rub active ingredients that are Categories I, II, and III. At the final information (59 FR 31402 at 31440). We
the subject of this document. monograph stage, FDA does not use the do not discuss food handler antiseptics
terms ‘‘Category I,’’ ‘‘Category II,’’ and further in this document, and this
A. Terminology Used in the OTC Drug ‘‘Category III.’’ Instead, the term document does not address the status of
Review Regulations ‘‘monograph conditions’’ is used in antiseptics for food industry use.
1. Proposed, Tentative Final, and Final place of Category I, and ‘‘nonmonograph The 1994 TFM did not distinguish
Monographs conditions’’ is used in place of between consumer antiseptic washes
Categories II and III. and rubs and healthcare antiseptic
To conform to terminology used in
the OTC Drug Review regulations B. Topical Antiseptics and Scope of washes and rubs. In the 2013 Consumer
(§ 330.10 (21 CFR 330.10)), the Document Antiseptic Wash proposed rule, we
advanced notice of proposed proposed that our evaluation of OTC
The OTC topical antimicrobial
rulemaking (ANPR) that was published antiseptic drug products be further
rulemaking encompasses a range of drug
in the Federal Register of September 13, subdivided into healthcare antiseptics
products that contain a number of active
1974 (39 FR 33103) (1974 ANPR), was and consumer antiseptics (78 FR 76444
ingredients and are labeled and
designated as a ‘‘proposed monograph.’’ at 76446). These categories are distinct
Similarly, the notices of proposed marketed for a variety of intended uses.
based on the proposed use setting, target
rulemaking, which were published in The 1974 ANPR for topical
population, and the fact that each
the Federal Register of January 6, 1978 antimicrobial products encompassed
products for both healthcare and setting presents a different level of risk
(43 FR 1210) (1978 TFM); the Federal for infection. In the 2013 Consumer
Register of June 17, 1994 (59 FR 31402) consumer use (39 FR 33103). The 1974
ANPR covered seven different intended Antiseptic Wash proposed rule (78 FR
(1994 TFM); the Federal Register of 76444 at 76446 to 76447) and the 2016
December 17, 2013 (78 FR 76444) (2013 uses for these products: (1)
Antimicrobial soap; (2) healthcare Consumer Antiseptic Rub proposed rule
Consumer Antiseptic Wash proposed (81 FR 42912 at 42915 to 42916), we
rule); the Federal Register of May 1, personnel hand wash; (3) patient
preoperative skin preparation; (4) skin proposed that our evaluation of OTC
2015 (80 FR 25166) (2015 Health Care consumer antiseptic drug products be
Antiseptic proposed rule); and the antiseptic; (5) skin wound cleanser; (6)
skin wound protectant; and (7) surgical further subdivided into consumer
Federal Register of June 30, 2016 (81 FR washes (products that are rinsed off
42912) (2016 Consumer Antiseptic Rub hand scrub (39 FR 33103 at 33140). FDA
subsequently identified skin antiseptics, with water, including hand washes and
proposed rule) were each designated as body washes) and consumer rubs
a TFM (see table 1 in section IV.A.). skin wound cleansers, and skin wound
protectants as antiseptics used primarily (products that are not rinsed off after
2. Category I, II, and III Classifications by consumers for first aid use and use, including hand rubs and
The OTC drug regulations in § 330.10 referred to them collectively as ‘‘first aid antibacterial wipes). This document
use the terms ‘‘Category I’’ (generally antiseptic drug products.’’ We does not address the status of OTC
recognized as safe and effective and not published a separate TFM covering first consumer antiseptic wash or healthcare
misbranded), ‘‘Category II’’ (not aid antiseptics in the Federal Register of antiseptic products.
generally recognized as safe and July 22, 1991 (56 FR 33644). We do not This document covers only OTC
effective or misbranded), and ‘‘Category discuss first aid antiseptics further in consumer antiseptic rubs. Completion of
III’’ (available data are insufficient to this document, and this document does the monograph for consumer antiseptic
classify as generally recognized as safe not address the status of first aid rubs and certain other monographs for
and effective, and further testing is antiseptics. the active ingredient triclosan are
necessary). Section 330.10 provides that The four remaining categories of subject to a Consent Decree entered by
any testing necessary to resolve the topical antimicrobials were addressed in the U.S. District Court for the Southern
safety or effectiveness issues that the 1994 TFM (59 FR 31402). The 1994 District of New York on November 21,
resulted in an initial Category III TFM covered: (1) Antiseptic hand wash 2013, in Natural Resources Defense
classification, and submission to FDA of (i.e., consumer hand wash); (2) Council, Inc. v. United States Food and
Drug Administration, et al., 10 Civ. 5690 received on the 2016 Consumer publications relevant to this document
(S.D.N.Y.). Antiseptic Rub proposed rule. are available at https://
IV. Background A. Significant Rulemakings Relevant to www.regulations.gov in FDA Docket No.
This Document 1975–N–0012 (formerly Docket No.
In this section, we describe the 1975–N–0183H and Docket No. FDA–
significant rulemakings and public A summary of the significant Federal 2015–N–0101).
meetings relevant to this document and Register publications relevant to this
discuss our response to comments document is provided in table 1. Other
TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO CONSUMER ANTISEPTIC DRUG PRODUCTS 1
Federal Register notice Information in notice
1974 ANPR (September 13, We published an ANPR to establish a monograph for OTC topical antimicrobial drug products, together with the
1974, 39 FR 33103). recommendations of the advisory review panel (the Panel) responsible for evaluating data on the active ingredi-
ents in this drug class.
1978 Antimicrobial TFM We published our tentative conclusions and proposed effectiveness testing for the drug product categories evalu-
(January 6, 1978, 43 FR ated by the Panel, reflecting our evaluation of the Panel’s recommendations and comments and data submitted
1210). in response to the Panel’s recommendations.
1991 First Aid TFM (July 22, We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic products. In the 1991
1991, 56 FR 33644). TFM, we proposed that first aid antiseptic drug products be indicated for the prevention of skin infections in
minor cuts, scrapes, and burns.
1994 Health Care Antiseptic We amended the 1978 TFM to establish a separate monograph for the group of products referred to as OTC top-
TFM (June 17, 1994, 59 ical healthcare antiseptic drug products. These antiseptics are generally intended for use by healthcare profes-
FR 31402). sionals.
In the 1994 TFM, we also recognized the need for antibacterial personal cleansing products for consumers to
help prevent cross-contamination from one person to another and proposed a new antiseptic category for con-
sumer use: Antiseptic hand wash.
2013 Consumer Antiseptic We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining whether
Wash TFM (December 17, OTC consumer antiseptic washes are GRAS/GRAE.
2013, 78 FR 76444). In the 2013 Consumer Antiseptic Wash TFM, we proposed that additional safety and effectiveness data are nec-
essary to support the safety and effectiveness of consumer antiseptic wash active ingredients.
2015 Health Care Antiseptic We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining whether
TFM (May 1, 2015, 80 FR OTC healthcare antiseptics are GRAS/GRAE.
25166). In the 2015 Health Care Antiseptic TFM, we proposed that additional data are necessary to support the safety
and effectiveness of healthcare antiseptic active ingredients.
2016 Consumer Antiseptic We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining whether
Rub TFM (June 30, 2016, OTC consumer antiseptic rubs are GRAS/GRAE.
81 FR 42912). In the 2016 Consumer Antiseptic Rub TFM, we proposed that additional safety and effectiveness data are nec-
essary to support the safety and effectiveness of consumer antiseptic rub active ingredients.
2016 Consumer Antiseptic We issued a final rule finding that certain active ingredients used in OTC consumer antiseptic wash products are
Wash Final Monograph not GRAS/GRAE.
(September 6, 2016, 81 We deferred further rulemaking on three specific active ingredients (benzalkonium chloride, benzethonium chlo-
FR 61106). ride, and chloroxylenol) used in OTC consumer antiseptic wash products to allow for the development and sub-
mission of new safety and effectiveness data to the record for those ingredients.
2017 Health Care Antiseptic We issued a final rule finding that certain active ingredients used in OTC healthcare antiseptic products are not
Final Monograph (Decem- GRAS/GRAE.
ber 20, 2017, 82 FR We deferred further rulemaking on six specific active ingredients (benzalkonium chloride, benzethonium chloride,
60474). chloroxylenol, ethyl alcohol, isopropyl alcohol and povidone iodine) used in OTC healthcare antiseptic products
to allow for the development and submission of new safety and effectiveness data to the record for those ingre-
dients.
1 The publications listed in table 1 can be found at FDA’s ‘‘Status of OTC Rulemakings’’ website available at https://www.fda.gov/Drugs/
DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications
dated after 1993 can also be found in the Federal Register at https://www.federalregister.gov.
B. Public Meetings Relevant to This been four meetings of the NDAC that are effectiveness. These meetings are
Document relevant to the discussion of OTC summarized in table 2.
In addition to the Federal Register consumer antiseptic rubs’ safety and
publications listed in table 1, there have
TABLE 2—PUBLIC MEETINGS RELEVANT TO CONSUMER ANTISEPTIC RUBS
Date and type of meeting Topic of discussion
January 1997; NDAC Meeting (Joint meeting with the Anti-Infective Antiseptic and antibiotic resistance in relation to an industry proposal
Drugs Advisory Committee) (January 6, 1997, 62 FR 764). for consumer and healthcare antiseptic effectiveness testing (Health
Care Continuum Model) (Refs. 1 and 2).
March 2005; NDAC Meeting (February 18, 2005, 70 FR 8376) ............. The use of surrogate endpoints and study design issues for the in vivo
testing of healthcare antiseptics (Ref. 3).
TABLE 2—PUBLIC MEETINGS RELEVANT TO CONSUMER ANTISEPTIC RUBS—Continued

Date and type of meeting Topic of discussion
October 2005; NDAC Meeting (September 15, 2005, 70 FR 54560) ..... Benefits and risks of consumer antiseptics. NDAC expressed concern
about the pervasive use of consumer antiseptic washes where there
are potential risks and no demonstrable benefit. To demonstrate a
clinical benefit, NDAC recommended clinical outcome studies to
show that antiseptic washes are superior to nonantibacterial soap
and water (Ref. 4).
November 2008; Public Feedback Meeting ............................................. Demonstration of the effectiveness of consumer antiseptics (Ref. 5).
September 2014; NDAC Meeting (July 29, 2014, 79 FR 44042) ............ Safety testing framework for healthcare antiseptic active ingredients
(Ref. 6).
C. Eligibility for the OTC Drug Review product labeling or a facsimile of active ingredient under any other OTC
An OTC drug is covered by the OTC labeling that documents the conditions drug monograph.
Drug Review if its conditions of use of marketing of a product before May
1. Eligible Active Ingredients
existed in the OTC drug marketplace on 1972 (see § 330.10(a)(2)). FDA considers
or before May 11, 1972 (37 FR 9464).1 a drug that is ineligible for inclusion in Table 3 lists the active ingredients
Conditions of use include, among other the OTC monograph system to be a new eligible for evaluation under the OTC
things, active ingredient, dosage form drug that requires FDA approval of an Drug Review for use in OTC consumer
and strength, route of administration, NDA or ANDA prior to marketing. The antiseptic rubs and provides the
and specific OTC use or indication of ineligibility of an active ingredient for classification proposed in the 1994 TFM
the product (see 21 CFR 330.14(a)). To evaluation under the OTC Drug Review and the classification proposed in the
determine eligibility for the OTC Drug for use in an OTC consumer antiseptic 2016 Consumer Antiseptic Rub
Review, FDA typically must have actual rub does not affect eligibility of that proposed rule.
TABLE 3—CLASSIFICATION OF OTC CONSUMER ANTISEPTIC RUB ACTIVE INGREDIENTS IN THE 1994 TFM AND IN THE
2016 PROPOSED RULE
1994 2016
Active ingredient TFM Proposed rule
proposal 1
Alcohol 60 to 95 percent ......................................................................................................................................... I 2 .................... IIISE 3.

Isopropyl alcohol 70 to 91.3 percent ...................................................................................................................... IIIE ................. IIISE.
Benzalkonium chloride ............................................................................................................................................ IIISE ............... IIISE.
1 Because the 1994 TFM did not describe antiseptic hand washes and rubs separately, the 1994 TFM classification was for use as an anti-
septic hand wash or healthcare antiseptic hand wash.
2 ‘‘I’’ denotes a classification that an active ingredient is GRAS/GRAE and not misbranded.
3 ‘‘III’’ denotes a classification that the available data are insufficient to classify the active ingredient as GRAS/GRAE. ‘‘S’’ denotes safety data
needed. ‘‘E’’ denotes effectiveness data needed.
In the 1994 TFM, alcohol was and effectiveness data for these three 2. Ineligible Active Ingredients
proposed to be classified as Category I, ingredients. Therefore, we do not make
isopropyl alcohol was proposed to be The following list includes those
a GRAS/GRAE determination for these
classified as Category IIIE, and active ingredients addressed in the 1994
three active ingredients in this
benzalkonium chloride was proposed to TFM for use in antiseptic hand washes
document. The monograph or or healthcare personnel hand washes
be classified as Category IIISE for use in nonmonograph status of these three
an antiseptic hand wash or healthcare and identified in the 2016 Consumer
ingredients will be addressed, either Antiseptic Rub proposed rule as having
personnel hand wash. However, in the after completion and analysis of studies
2016 Consumer Antiseptic Rub inadequate evidence of eligibility for
to address the safety and effectiveness evaluation under the OTC Drug Review
proposed rule, we proposed to classify data gaps of these ingredients or at
all three ingredients as Category IIISE for use in an OTC consumer antiseptic
another time, if these studies are not rub:
for use in a consumer antiseptic rub completed. As discussed below, this
because additional effectiveness and
document describes the studies • Benzethonium chloride
safety data are needed to classify each • Chloroxylenol
necessary as a scientific matter for the
ingredient as GRAS/GRAE for this use.
Agency to determine whether an active • Chlorhexidine gluconate 2
FDA has deferred further rulemaking ingredient is GRAS/GRAE for use in • Cloflucarban
on these three active ingredients for use
in OTC consumer antiseptic rubs to
consumer antiseptic rubs. • Fluorosalan
allow for the development and • Hexachlorophene
submission to the record of new safety • Hexylresorcinol
1 Also, note that drugs initially marketed in the Review based on submission of a time and extent antiseptic use and was not included in the 1994
United States after the OTC Drug Review began in application. (See 21 CFR 330.14.) TFM (59 FR 31402 at 31413). We have not received
1972 and drugs without any U.S. marketing 2 Chlorhexidine gluconate 4 percent aqueous any new information since the 1994 TFM
experience can be considered under the OTC Drug solution was also found to be ineligible for demonstrating that this active ingredient is eligible
inclusion in the monograph for any healthcare for the topical antimicrobial monograph.
• Iodine complex (ammonium ether that if appropriate documentation was This meant that the lower bound of the
sulfate and polyoxyethylene sorbitan submitted for a proposed ineligible 95 percent confidence interval for the
monolaurate) active ingredient, we could determine proportion of subjects who met the log
• Iodine complex (phosphate ester of that the active ingredient was eligible reduction criteria was expected to be at
alkylaryloxy polyethylene glycol) for evaluation under the OTC Drug least 70 percent.
• Methylbenzethonium chloride Review for use in an OTC consumer Consistent with the 1994 TFM, the
• Nonylphenoxypoly (ethyleneoxy) antiseptic rub. We have not received 2015 Health Care Antiseptic proposed
ethanoliodine any information or documentation for rule, the 2016 Consumer Antiseptic Rub
• Phenol (equal to or less than 1.5 the 28 active ingredients identified as proposed rule, and the 2017 Health Care
percent or greater than 1.5 percent) ineligible in the 2016 Consumer Antiseptic FR, we find that bacterial log
• Poloxamer iodine complex Antiseptic Rub proposed rule since the reduction studies should continue to be
• Povidone-iodine 5 to 10 percent proposed rule’s publication used to demonstrate that an active
• Secondary amyltricresols demonstrating that these active ingredient is effective for use in a
• Sodium oxychlorosene ingredients are eligible for evaluation consumer antiseptic rub product. Also,
• Tribromsalan consistent with the 2015 Health Care
• Triclocarban under the OTC Drug Review for
inclusion in the OTC consumer Antiseptic proposed rule, the 2016
• Triclosan
• Triple dye antiseptic rub monograph. Accordingly, Consumer Antiseptic Rub proposed
• Undecoylium chloride iodine OTC consumer antiseptic rub drug rule, and the 2017 Health Care
complex products containing any of these Antiseptic final rule, subjects should be
ineligible active ingredients are new randomized to a three-arm study: Test,
In addition, as previously described drugs under section 201(p) of the active control, and negative control (the
in the 2016 Consumer Antiseptic Rub Federal Food, Drug, and Cosmetic Act test product’s vehicle or saline
proposed rule, FDA received several (FD&C Act) (21 U.S.C. 321(p)) for which solution). However, as outlined in the
submissions in response to the 1994 approved applications under section consumer antiseptic rub deferral letters
TFM requesting that the compounds 505 of the FD&C Act (21 U.S.C. 355) and (Ref. 7) and based on comments
identified below be included in the part 314 (21 CFR part 314) of the submitted on the 2015 Health Care
monograph: regulations are required for marketing Antiseptic proposed rule and the
• Polyhexamethylene biguanide and which may be misbranded under Agency’s further evaluation of
• Benzalkonium cetyl phosphate section 502 of the FD&C Act (21 U.S.C. additional data, we have updated the
• Cetylpyridinium chloride 352). statistical analysis related to the log
• Salicylic acid reduction criteria for classifying
• Sodium hypochlorite D. Updated Statistical Analysis for consumer antiseptic rub active
• Tea tree oil Efficacy ingredients as GRAE. This updated
• Combination of potassium vegetable In the 1994 TFM, FDA recommended statistical analysis is consistent with the
oil solution, phosphate sequestering that the general effectiveness of statistical analysis set forth in the 2017
agent, and triethanolamine antiseptics be assessed in several ways, Health Care Antiseptic final rule.
These compounds were not addressed including by conducting clinical Rather than using only a change in
prior to the 1994 TFM in FDA simulation studies with the surrogate bacterial count from baseline, the
documents related to the topical endpoint of the number of bacteria updated analysis uses the average
antimicrobial monograph and were not removed from the skin. In the 2015 treatment effect (ATE), an estimated
evaluated for antiseptic hand wash use Health Care Antiseptic proposed rule difference of the effect of two treatments
by the Advisory Review Panel on OTC and the 2016 Consumer Antiseptic Rub correcting for baseline count. The ATE
Topical Antimicrobial I Drug Products proposed rule, FDA made revisions to is estimated from a linear regression of
(Antimicrobial I Panel), which was the the effectiveness criteria proposed in the post-treatment bacterial count (log10
advisory review panel responsible for 1994 TFM, while continuing to scale) on the additive effect of a
evaluating data on the active ingredients recommend that bacterial log reduction treatment indicator and the baseline or
in this drug class. studies be used to demonstrate that an pre-treatment measurement (log10 scale).
In addition, in the 1994 TFM (59 FR active ingredient is GRAE for use in a The updated analysis is designed to
31402 at 31435) FDA proposed that the consumer antiseptic rub product. FDA assess whether the ATEs across subjects
active ingredients fluorosalan, recommended that these bacterial log meet specific conditions of superiority
hexachlorophene, phenol (greater than reduction studies: (1) Include both a and non-inferiority, rather than whether
1.5 percent), and tribromsalan be negative control (test product vehicle or the percentage of subjects who meet a
classified as not GRAS/GRAE for the saline solution) and an active control specific threshold significantly exceeds
uses referred to in the 1994 TFM as (an FDA-approved product); (2) have an 70 percent. Under the updated analysis,
antiseptic hand wash and healthcare adequate sample size to show that the products must show non-inferiority of
personnel hand wash. In the 2016 test product is superior to its negative test product to active control by a
Consumer Antiseptic Rub proposed control; (3) incorporate the use of an margin of 0.5 (log10 scale) and
rule, FDA explained that it would not appropriate neutralizer and a superiority of test product to negative
discuss the efficacy and safety demonstration of neutralizer validation; control by a margin of 1.5 (log10 scale).
information regarding these ingredients and (4) include an analysis of the In the conditions below, the ATE of the
that had been submitted to the proportion of subjects who meet the test product compared to the negative
rulemaking because none of the four recommended log reduction criteria control is defined as the contrast of
active ingredients had adequate based on a two-sided statistical test for treatment effect of negative control
evidence of eligibility for evaluation superiority to negative control and a 95 minus the treatment effect of the test
under the OTC Drug Review for use in percent confidence interval approach drug in the linear regression. Likewise,
an OTC consumer antiseptic rub (81 FR (81 FR 42912 at 42921 to 42922). FDA the ATE of the active control compared
42912 at 42918). also recommended that the success rate to the test product is defined as the
FDA also explained in the 2016 or responder rate of the test product be contrast of treatment effect of test
Consumer Antiseptic Rub proposed rule significantly higher than 70 percent. product minus the treatment effect of
the active control in the linear laboratory facilities by independent consumer antiseptic rub product can be
regression. principal investigators. used when hands are visibly soiled
Superiority to negative control by a could depend on the particular
specific margin is needed because our V. Comments on the Proposed Rule and
product’s final formulation.
evaluation suggests that application of a FDA Response We also decline to incorporate the
negative control, whether the test A. Introduction concept of practicality into the
product’s vehicle or saline, may exhibit In response to the 2016 Consumer consumer antiseptic rub’s definition. It
some minimal antimicrobial properties. Antiseptic Rub proposed rule, we is unclear what it means to say that soap
Thus, using superiority to negative received approximately 47 comments and water are not ‘‘practical,’’ or how
control by those margins will help from an animal rights organization, not ‘‘practical’’ differs from not
ensure that we can appropriately assess healthcare professionals, a ‘‘available.’’ We do not think that
the effectiveness of the antimicrobial manufacturer, trade associations, and adding the word ‘‘practical’’ helps to
products. The margins we identify in individuals. We also received additional define the category of consumer
this section were derived from review data and information for certain antiseptic rubs or to differentiate
and analysis of existing data and may be deferred consumer antiseptic rub active consumer antiseptic rubs from other
revised as data gaps on deferred ingredients. products. For these reasons, we will
antimicrobial products are filled. We describe and respond to the continue to define consumer antiseptic
Because of existing data gaps, we also comments in sections V.B. through V.E. rubs as products that are intended to be
require the deferred ingredient to show We have numbered each comment to used when soap and water are not
non-inferiority to active controls by a help distinguish among the different available and are left on and not rinsed
0.5 margin (log10 scale). comments. We have grouped similar off with water (81 FR 42912 at 42913).
Accordingly, based on the updated comments together under the same
analysis, the bacterial log reduction 2. GRAS/GRAE Classification of Alcohol
number, and in some cases, we have
studies used to assess whether an active (Comment 2) Several comments
separated different issues discussed in
ingredient is effective for use in requested that FDA reconsider its
the same comment and designated them
consumer antiseptic rubs should proposal in the 2016 Consumer
as distinct comments for purposes of
include the following: Antiseptic Rub proposed rule to classify
our responses. The number assigned to
• The test product should be non- alcohol as a Category III (available data
each comment or comment topic is
inferior to an FDA-approved antiseptic are insufficient to classify as safe and
purely for organizational purposes and
rub as active control with a 0.5 margin effective, and further testing is
does not signify the comment’s value,
(log10 scale). That is, we expect the necessary) active ingredient. In the 1994
importance, or the order in which TFM, alcohol was proposed to be
upper bound of the 95 percent
comments were received. classified as a Category I (generally
confidence interval of the ATE of the
active control compared to the test B. General Comments on the Proposed recognized as safe and effective and not
product to be less than 0.5 (log10 scale). Rule and FDA Response misbranded) topical antiseptic
An active control is not intended to ingredient for certain indications. Two
1. Definition of Consumer Antiseptic comments argued that FDA has
validate the study conduct or to show
Rubs provided no data to indicate that there
superiority of the test drug product but
to show that the test drug product is not (Comment 1) We received comments is a safety or efficacy concern or issue
inferior to the control. Non-inferiority to asking FDA to revise the definition of with alcohol. These comments noted
active control should be met on each consumer antiseptic rubs. In the 2016 that during the September 3, 2014,
hand within 5 minutes after a single rub Consumer Antiseptic Rub proposed NDAC meeting, several NDAC members
for the consumer antiseptic rub rule, we stated that consumer antiseptic argued in favor of continuing to
indication. rubs are products that are intended to be categorize alcohol as Category I while
• The test product should be superior used when soap and water are not further testing is conducted to fill the
to the negative control by a margin of available and are left on and not rinsed data gaps about its safety.
1.5 (log10 scale). That is, we expect the off with water (81 FR 42912 at 42913). (Response 2) As we explained in the
lower bound of the 95 percent These comments asked FDA to define 2017 Health Care Antiseptic final rule,
confidence interval of the ATE of the consumer antiseptic rubs as products we classify ingredients as Category I,
test product compared to the negative ‘‘that are intended for use when hands Category II (not generally recognized as
control to be greater than 1.5 (log10 are not visibly soiled, or when soap and safe and effective or misbranded), and
scale). In cases where the vehicle cannot water are not practical or available and Category III until the final monograph
be used as a negative control, saline are not intended to be rinsed off with stage, at which point we use the term
solution can be used. Based on our water.’’ ‘‘monograph conditions’’ in place of
evaluation of the existing data, for the (Response 1) We decline to revise the Category I, and the term
consumer antiseptic rub indication a definition of consumer antiseptic rubs ‘‘nonmonograph conditions’’ in place of
superiority margin of 1.5 (log10 scale) to add information about using or not Categories II and III (82 FR 60474 at
should be met on each hand within 5 using consumer antiseptic rubs when 60482). In the 1994 TFM, alcohol was
minutes after a single rub. hands are visibly soiled. In general, proposed to be classified as Category I
• Include a minimum sample size of information about when and how to use for use in ‘‘antiseptic hand wash’’
100 subjects per treatment arm. The a drug product is contained in the products, which included consumer
study can have a larger sample size in product’s label. In this case, the label is antiseptic rubs (59 FR 31402 at 31433).
each treatment arm to meet criteria for the appropriate place for information In the 2016 Consumer Antiseptic Rub
about using or not using consumer proposed rule, we changed the proposed
non-inferiority and superiority after

assessment of variability. antiseptic rub products when hands are classification of alcohol for use in
• Conduct two adequate and well- visibly soiled. Integrating information consumer antiseptic rubs from Category
controlled clinical simulation pivotal about such use into the definition of I to III, because we found that there
studies for the consumer antiseptic rub consumer antiseptic rubs could be were not enough data on alcohol to meet
indication at two separate independent problematic because whether a our proposed safety data requirements
(81 FR 42912 at 42918 to 42919, 42928). submission to the record of new safety ingredient in the applicable final
We explained that there had been many and effectiveness data for these monograph.
important scientific developments since ingredients. The deferred active
5. Implementation and Compliance
1994 that affected our evaluation of the ingredients are benzalkonium chloride,
safety of the active ingredients in alcohol (also referred to as ethanol or (Comment 5) We received comments
consumer antiseptic rub products and ethyl alcohol), and isopropyl alcohol. stating that one benefit of the consumer
that this, in turn, had caused us to For each active ingredient, FDA has antiseptic rub rulemaking is that
reassess the data necessary to support a deferred rulemaking for 1 year, with the consumer antiseptic rub products
GRAS determination (81 FR 42912 at possibility of renewal, which allows the containing potentially harmful active
42923). These developments include Agency to monitor the continued ingredients will be removed from the
new information regarding systemic progress of the studies being conducted market. One comment asked what steps
exposure to antiseptic active (Ref. 7). FDA will take to remove ‘‘substandard’’
ingredients, the need to evaluate the products from the market.
potential for widespread antiseptic use 4. Labeling (Response 5) In section VII, we
to promote the development of (Comment 4) One comment stated explain that we recognize that
antibiotic-resistant bacteria, and that the labeling of consumer antiseptic manufacturers will need time to comply
improved study designs that are more with this document. Thus, as proposed
rub products should contain the
capable of detecting a potential safety in the 2016 Consumer Antiseptic Rub
established name of the drug and
risk. In the case of alcohol, we proposed rule (81 FR 42912 at 42930 to
identify the product using ‘‘Antiseptic
explained that the available data 42931), this document will be effective
Rub,’’ ‘‘Antiseptic Hand Rub,’’
characterizing the level of dermal 1 year after the date of the document’s
‘‘Antimicrobial rub,’’ ‘‘Antimicrobial
absorption and expected systemic publication in the Federal Register. On
hand rub,’’ ‘‘Hand Sanitizer,’’
exposure in adults as a result of topical or after that date, any OTC consumer
‘‘Antiseptic Hand Sanitizer,’’ or
use of alcohol-containing antiseptics do antiseptic rub drug product containing
‘‘Antimicrobial Hand Sanitizer.’’ The
not cover maximal use of these products an active ingredient that we have found
comment contended that ‘‘Hand
(81 FR 42912 at 42928). Therefore, we in this document to be ineligible for
Sanitizer’’ is the term that is the most consideration under the OTC Drug
determined that the data regarding the recognized and understood by
safety of alcohol were insufficient to Review for the OTC consumer antiseptic
consumers and that a change in rub monograph cannot be introduced or
make a GRAS determination without terminology could cause confusion. The
human pharmacokinetic (PK) studies delivered for introduction into interstate
comment also recommended that FDA commerce unless it is the subject of an
under maximal usage trial (MUsT) clarify that the Drug Facts label for
conditions when applied topically, approved NDA or ANDA. FDA strives to
consumer antiseptic rubs can use the minimize risk to consumers by
including documentation of validation header ‘‘Use/s’’ in place of ‘‘Indication,’’
of the methods used to measure alcohol monitoring the market and, where
since ‘‘Use’’ is more easily understood appropriate, undertaking efforts to
and its metabolites. by consumers, and also recommended remove violative OTC drug products
3. Requests for Deferrals of Final certain terminology to describe the from the market.
Rulemaking products’ use. In addition, the comment
proposed that the ‘‘Directions’’ section 6. Public Education
(Comment 3) We received comments
requesting that FDA defer rulemaking of the Drug Facts label for consumer (Comment 6) A number of comments
on the three active ingredients eligible antiseptic rubs reflect the parameters included questions or concerns about
for use in OTC consumer antiseptic rub used when product efficacy was the ways in which FDA communicates
products to allow for the development demonstrated. Other comments with consumers about the antiseptic
and submission to the record of new proposed that the Directions section rulemakings. One comment asked how
safety and effectiveness data for these include clear and specific instructions the general public is notified of the
active ingredients. One comment for proper use, such as the number of Agency’s findings. Another comment
asserted that the studies FDA proposed pumps required to adequately coat the argued that educating the public on
could take several years to design, hand, as well as information on antiseptic products is necessary because
execute, analyze, and report, and products’ shelf lives. the products’ labeling lacks specificity
requested that FDA defer rulemaking for (Response 4) As we explained in the and because consumers may not take
alcohol and benzalkonium chloride. 2016 Consumer Antiseptic Rub the time to read the labeling. Another
Another comment contended that the proposed rule, the labeling for consumer comment asked FDA to be cautious in
differences in the testing requirements antiseptic rub products containing a its communications with consumers
between the 1994 TFM and the 2016 particular active ingredient will be about the Agency’s work on the
Consumer Antiseptic Rub proposed rule addressed as part of the final rule if FDA antiseptic monographs. This comment
warrant an extension of time to determines that the active ingredient is pointed to a September 12, 2016,
determine essential studies that may be GRAS/GRAE (81 FR 42912 at 42913). posting on FDA’s website entitled
needed for isopropyl alcohol, protocols Because all three of the active ‘‘Antibacterial Soap? You Can Skip It—
for those studies, review of any data ingredients that are eligible for Use Plain Soap and Water.’’ The
generated, and submission of the data to evaluation for use in consumer comment argued that the headline
FDA. antiseptic rubs have been granted misleadingly implies that antibacterial
(Response 3) As explained earlier, in deferrals, and FDA has not yet made a soaps in any setting (and also, by
response to several requests submitted GRAS/GRAE determination on these implication, potentially any topical
to the 2016 Consumer Antiseptic Rub ingredients, we do not address their antimicrobial product) do not work.
proposed rule, FDA has deferred further labeling in this document. If any of the This comment also criticized FDA’s
rulemaking on the three active three active ingredients are claim that antibacterial soaps ‘‘may do
ingredients eligible for use in OTC subsequently found to be GRAS/GRAE, more harm than good over the long
consumer antiseptic rub products to we will address the labeling for term.’’ The comment asked that FDA be
allow for the development and products containing that active clear in its communications that alcohol
(when used as an active ingredient in this, the comments asked FDA to the relevant data gaps are unlikely to be
topical antiseptic products) has no consolidate MUsT requirements and sufficient.
known safety signals and there is no testing between the different indications The Agency has not specified ATCC
reason to believe that alcohol-based and the different monographs to strain numbers for H. influenzae, B.
hand sanitizers are associated with minimize the number of trials needed. fragilis, and Enterobacter species in
creating ‘‘supergerms’’ or antibacterial (Response 7) Whenever it is order to provide manufacturers with
resistant organisms. scientifically appropriate to do so, options for conducting the necessary
(Response 6) FDA communicates publicly available efficacy and safety studies. Manufacturers may select any
about its various activities, including data developed to support one use of an available strain of these bacteria. For
the findings it has made as part of the antiseptic active ingredient may be cross MBC or MIC testing, 25 representative
antiseptic rulemaking, in several ways. referenced to support other uses. clinical isolates and 25 reference
Each of the various antiseptic (ATCC) strains of each one of these
Generation of duplicative data is not
rulemakings has an official docket, organisms (H. influenzae, B. fragilis, and
necessary. We agree that the PK data
which is publicly available and can be Enterobacter species) are necessary. For
generated from a MUsT study that is
accessed at https://www.regulations.gov. time-kill testing, any one ATCC strain
sufficient to support a healthcare
These dockets contain the proposed and for these three organisms is sufficient.
antiseptic indication will also be
final rules in which FDA sets forth its
sufficient to support a consumer 2. In Vivo Testing
findings, along with various supporting
antiseptic indication, because the (Comment 9) We received comments
documents. FDA also communicates
maximal usage across consumer settings on the in vivo efficacy testing
with the public through our website.
is lower than the maximal usage in a requirements that the Agency proposed
The entire rulemaking history for OTC
healthcare setting. in the 2016 Consumer Antiseptic Rub
antiseptic products can be found at
https://www.fda.gov/Drugs/ C. Comments on Effectiveness and FDA proposed rule for evaluating active
DevelopmentApprovalProcess/ Response ingredients for use in consumer
DevelopmentResources/Over-the- antiseptic rubs (81 FR 42912 at 42921).
CounterOTCDrugs/Statusof 1. In Vitro Testing One comment asked that we confirm
OTCRulemakings/ucm070821.htm. In (Comment 8) One comment requested that the following test conditions are
addition, FDA communicates with that FDA clarify the in vitro testing suitable:
Congress, consumers, industry, and requirements that the Agency proposed • Two pivotal studies would be
other stakeholders, such as patient in the 2016 Consumer Antiseptic Rub conducted.
advocacy groups and professional • A single use wash would be
proposed rule for evaluating active
associations, through press releases and applied.
ingredients for use in consumer • A physiological saline solution
our accounts on social media sites, antiseptic rubs (81 FR 42912 at 42921).
including Facebook, Twitter, and would be used as the control.
The comment asked whether FDA is • Avagard, the only healthcare
LinkedIn. We appreciate and will take requiring minimum bactericidal
under consideration the commenters’ personnel hand rub approved under an
concentration (MBC), minimum NDA would be used as the active
suggestions regarding our inhibitory concentration (MIC), and
communications with consumers about control, if pilot studies confirm its
time-kill testing using the bacteria appropriateness.
the antiseptic rulemakings. specified in the 2016 Consumer (Response 9) Based on the updated
7. Overlapping Data Requirements and Antiseptic Rub proposed rule (81 FR statistical analysis for efficacy that we
Collections 42912 at 42921). The comment then outline in section IV.D., we confirm that
(Comment 7) We received comments asked whether time-kill testing alone two adequate and well-controlled
asking that data that are collected to fill would suffice to meet the in vitro testing clinical simulation pivotal studies
in a data gap for one antiseptic requirements. Finally, the comment should be conducted for the consumer
indication or in response to one asked why FDA did not provide an antiseptic rub indication at two separate
proposed or final rule also be applied to American Type Culture Collection independent laboratory facilities by
fill in data gaps for other antiseptic (ATCC) number for the three strains of independent principal investigators.
indications or rules. The comments gram-negative bacteria specified in the These studies should include a
stated that studies conducted and data 2016 Consumer Antiseptic Rub minimum sample size of 100 subjects
submitted to support a finding that an proposed rule—Haemophilus per treatment arm for each of the
active ingredient is GRAS/GRAE for a influenzae, Bacteroides fragilis, and deferred ingredients (alcohol,
healthcare antiseptic indication or for Enterobacter species. benzalkonium chloride, and isopropyl
use as a consumer antiseptic wash (Response 8) The in vitro testing alcohol). This sample size will ensure
should also provide sufficient support requirements for consumer antiseptic that the ATE will be estimated precisely
for a finding that the ingredient is rubs are specified in the 2016 Consumer for the deferred ingredients and can be
GRAS/GRAE for use as a consumer Antiseptic Rub proposed rule (81 FR used for future reference in final
antiseptic rub. One comment argued 42912 at 42921). We require MBC or product monographs. To determine the
that safety and efficacy data submitted MIC testing of 25 representative clinical minimum sample size, FDA analyzed
for the healthcare personnel hand rub isolates and 25 reference (e.g., ATCC) several studies that included a wide
use will be particularly relevant to the strains of each of the microorganisms range of sample sizes and concluded
consumer antiseptic hand rub use. The listed in section VII.B.1 of the 2016 that a minimum of 100 subjects is
comments specifically anticipated that Consumer Antiseptic Rub proposed rule appropriate to support the external
MUsT studies performed to support (81 FR 42912 at 42921). We also require validity of the results. We note that
healthcare indications would also time-kill testing of each microorganism establishing a minimum sample size of
support consumer indications, because and ATCC strain listed in section 100 subjects per study arm was not
maximal usage in a healthcare setting VII.B.1 of the 2016 Consumer Antiseptic solely based on statistical
would exceed maximal usage in the Rub proposed rule (81 FR 42912 at considerations; multiple factors,
various consumer settings. Because of 42921). Alternative approaches to filling including robustness and sensitivity of
log reduction to experimental for the three deferred antiseptic active to require additional safety data on the
conditions, were taken into account. ingredients for use in consumer fact that systemic exposure is higher
The study could have a larger sample antiseptic rub products. We are than previously thought, and new
size to meet the criteria for non- currently discussing with manufacturers information is available about the
inferiority and superiority after an and trade organizations that requested potential risks from systemic absorption
assessment of variability. the deferrals how these test methods and long-term exposure (80 FR 42912 at
We also confirm that it is appropriate may be used to meet the current 42923). The comment argued that before
to study a single rub application of the effectiveness criteria (see Docket Nos. FDA could require additional safety
active ingredient being tested for use as FDA–2015–N–0101 and FDA–2016–N– data, it would need to present
a consumer antiseptic rub. In the 2016 0124 at https://www.regulations.gov). ‘‘definitive evidence’’ that systemic
Consumer Antiseptic Rub proposed (Comment 11) Comments were exposure is higher than previously
rule, we proposed revisions to the log submitted that addressed the testing thought. The comment also argued that
reduction criteria for consumer requirements for the final formulations the evidence should consist of either in
antiseptic rubs based on the of specific consumer antiseptic rub vitro or dose-dependent data, and not
recommendations of the March 2005 products. Comments argued that neither risk, because, the comment explained,
NDAC meeting and comments to the MIC nor MBC testing should be the commenter was unaware of FDA’s
1994 TFM, which argued that the necessary for final formulations. The current thinking regarding risk
demonstration of a cumulative comments contended that an in vitro assessment.
antiseptic effect for these products is time-kill study against an appropriate (Response 12) We do not agree that
unnecessary (81 FR 42912 at 42922). We list of relevant microorganisms would FDA can only require additional safety
agreed that the critical element of suffice; one comment set forth specific data if there is ‘‘definitive evidence’’ in
effectiveness is that a product must be recommendations for the conduct of the form of in vitro or dose-dependent
effective after the first application such a study. data that systemic exposure is higher
because that represents the way in With regard to in vivo efficacy testing than we believed it to be when the 1994
which consumer antiseptic hand rubs requirements, comments argued that TFM was published. In the 2016
are used. Given that we are no longer full-scale pivotal studies of final Consumer Antiseptic Rub proposed
requiring a cumulative antiseptic effect, formulations should not be necessary, rule, we explained that, since the 1994
the efficacy criteria were revised to because less burdensome testing can TFM was published, new data have
reflect a single product application. confirm that a product’s formulation has become available indicating that
Finally, as noted in section IV.D., not inhibited the activity of the active systemic exposure to topical antiseptic
with regard to the negative control used ingredient. Comments suggested active ingredients may be greater than
in the studies, saline solution is confirmatory in vivo testing comparing previously thought. Because of advances
appropriate, but only if the test vehicle a finally formulated product to an active in technology, our ability to detect
cannot be used. With regard to the control after a single use. One comment antiseptic active ingredients in body
active control used in the studies, an argued that an active ingredient that was fluids such as serum and urine is greater
FDA-approved antiseptic rub product found to be GRAS/GRAE should be the than it was in 1994. For example,
should be selected. We have discussed active control, not an approved product. studies have shown detectable blood
and will continue to discuss the The comment noted that the only alcohol levels after use of alcohol-
selection of an appropriate active approved alcohol-based hand sanitizer containing hand rubs (Refs. 8 to 10).
control with the manufacturers and has two active ingredients. Another Given the frequent repeated use of
trade organizations that requested the consumer antiseptic rubs, systemic
comment proposed a specific study
deferrals for alcohol, benzalkonium exposure may occur. Although some
design with recommended success
chloride, and isopropyl alcohol (see systemic exposure data exist for all
criteria.
Docket Nos. FDA–2015–N–0101 and Finally, one comment recommended three deferred consumer antiseptic rub
FDA–2016–N–0124 at https:// active ingredients, data on systemic
that a dermatological evaluation be
www.regulations.gov). absorption after maximal use are
conducted on finally formulated
(Comment 10) Comments proposed lacking. We believe that the degree of
that the Agency recognize specific consumer antiseptic rub products to
ensure skin safety. systemic exposure should be
ASTM (American Society for Testing determined, and its consequences
(Response 11) In this document, we
and Materials International) protocols as assessed, to support our risk-benefit
do not find any active ingredients
standardized test methods for analysis for consumer antiseptic rub
demonstrating that an active ingredient GRAS/GRAE for use as a consumer
antiseptic rub. As a result, this use.
is GRAE for use in consumer (Comment 13) Some comments
antiseptics. These ASTM protocols document does not specifically address
argued that FDA should do a more
include ASTM E2755–15 ‘‘Standard requirements for anticipated final
robust analysis of existing safety data
Test Method for Determining the formulation testing. The testing
about human exposure and risk and that
Bacteria-Eliminating Effectiveness of requirements for finally formulated
this analysis should precede any
Healthcare Personnel Hand Rub products containing one of the three proposal requiring additional testing.
Formulations Using Hands of Adults,’’ deferred active ingredients will be Comments also argued that, in declining
ASTM E1054–08 ‘‘Standard Test addressed after one or more of the active to find ingredients GRAS based on
Methods for Evaluation of Inactivators ingredients are found to be GRAS/GRAE existing information, FDA is
of Antimicrobial Agents’’, and ASTM for use in consumer antiseptic rub inappropriately discounting the
E2783–11 ‘‘Standard Test Method for products. significant human marketing experience
and global acceptance of consumer
Assessment of Antimicrobial Activity D. Comments on Safety and FDA

for Water Miscible Compounds Using a Response antiseptic hand rub products and the
Time-Kill Procedure.’’ low incidence of adverse events. The
(Response 10) We have reviewed 1. Need for Additional Safety Data comments assert that the low incidence
these test methods and believe they may (Comment 12) One comment objected of adverse events is evidenced by the
be useful to help establish GRAE status to the fact that FDA based its decision fact that FDA’s Safety Information and
Adverse Event Reporting Program, study design has been refined into its proposed rule, no dermal
MedWatch, contains no safety-related current state. Moreover, the MUsT is a carcinogenicity studies of benzalkonium
complaints related to topical antiseptic published methodology that has been chloride have been submitted to FDA
products, and by the fact that FDA has presented at both national and (81 FR 42912 at 42929). Although, as the
not issued any safety alerts regarding international meetings. We also comment states, we have data generated
such products. A comment also stated explained that we understand and by two oral carcinogenicity studies, the
that the Nurses’ Health Studies, which recognize the potential of PK and PBPK potential for topically applied
are a series of long-term studies of modeling. FDA has considered these benzalkonium chloride to cause skin
health outcomes in several large cohorts options and others and has concluded cancer remains unstudied. There are no
of nurses, provide evidence of the safety that currently, they are not validated validated methods currently known to
of topical antiseptics. The comment adequately to substitute for the MUsT the Agency for predicting dermal
asserted that these studies did not show described in the 2016 Consumer carcinogenicity risk from data generated
any evidence that the use of topical Antiseptic Rub proposed rule (81 FR in studies that employed a non-dermal
antiseptic products leads to adverse 42912 at 42923 to 42924) and the 2015 route of administration. As we
health outcomes in nurses. Health Care Antiseptic proposed rule explained in the 2016 Consumer
(Response 13) FDA summarized the (80 FR 25166 at 25182). FDA has been Antiseptic Rub proposed rule, the
existing data and information on the reviewing the MUsT protocol designs magnitude of exposure to the skin from
three deferred active ingredients submitted by the manufacturers and a topical product can be much higher
alcohol, benzalkonium chloride, and trade organizations that requested than would be covered by systemic
isopropyl alcohol in the 2016 Consumer deferrals of the three consumer studies (81 FR 42912 at 42926). In
Antiseptic Rub proposed rule (81 FR antiseptic rub active ingredients and is addition, systemic exposure to the
42912 at 42927 to 42930). As explained currently discussing protocol design parent compound and metabolites can
in the 2016 Consumer Antiseptic Rub issues with these manufacturers and differ significantly for a dermally
proposed rule, the existing data and trade organizations. applied product because the skin has
information support the conclusion that With regard to the recommendation metabolic capability and first-pass
there is the potential for systemic that FDA provide guidance on MUsT metabolism is bypassed via this route of
exposure to antiseptic active ingredients studies, in May 2018 the Agency issued administration (81 FR 42912 at 42926).
through repeated dermal applications. a draft guidance for industry entitled Data on the potential for benzalkonium
At the same time, we lack the PK data ‘‘Maximal Usage Trials for Topical chloride to induce a neoplastic response
that would tell us precisely the degree Active Ingredients Being Considered for in the skin with repeated dermal
of systemic exposure under maximal Inclusion in an Over-The-Counter application are necessary in order to
use conditions. In addition, in vivo Monograph: Study Elements and assess the safety of benzalkonium
animal safety and toxicokinetic data are Considerations’’ (Ref. 11). The guidance, chloride for use in consumer antiseptic
lacking for some ingredients. Both when finalized, will outline FDA’s rub products.
human and animal data are needed to recommendations for designing and
(Comment 16) One comment stated
determine the safety margin for OTC conducting a MUsT, which, based on
that there are data suggesting that some
human use. If there is publicly available input from the NDAC, FDA has
antiseptic active ingredients have
data or information regarding the three determined is generally important to
hormonal effects. The comment asked
deferred active ingredients that FDA has support a GRAS/GRAE determination
not found or has overlooked, that for a topical active ingredient. The why products containing active
information can be submitted to the guidance, when finalized, will address ingredients with hormonal effects are
docket and considered by the Agency. critical study elements, data analysis, still on the market.
(Comment 14) One comment argued and considerations for special topic (Response 16) As we explained in the
that FDA should consider the level of areas (e.g., pediatrics, geriatrics). The 2016 Consumer Antiseptic Rub
human exposure to each of the guidance, when finalized, will also proposed rule, with the exception of
antimicrobial active ingredients and encourage study sponsors to seek human pharmacokinetic data under
assess the potential for harm from those feedback from FDA on their overall maximal use conditions, there are
exposures prior to determining the need approach and the design of a particular adequate safety data to determine that
for additional safety data. The comment study. alcohol is GRAS (81 FR 42912 at 42928).
states that in assessing exposure to (Comment 15) One comment argued This includes adequate data on the
active ingredients in consumer that FDA should not require additional hormonal effects of alcohol in animals
antiseptic rub products, FDA should carcinogenicity studies for and humans. Similarly, although there
allow alternative methods to MUsT benzalkonium chloride. This comment are other gaps in the safety data for
studies, including physiologically based stated that a good quality systemic benzalkonium chloride, there are
pharmacokinetic (PBPK) models and carcinogenicity data set exists for adequate data to make a determination
potentially other animal or human benzalkonium chloride, along with data that benzalkonium chloride does not
studies. The comment also states that from in vitro genetic toxicology studies. have hormonal effects (81 FR 42912 at
FDA should provide additional The comment contended that, given that 42928 to 42930). With regard to
guidance on how a MUsT study may be no tumors developed in an oral study of isopropyl alcohol, the existing data are
conducted in a reasonable manner. the product, and provided that good not adequate to characterize its potential
(Response 14) In the 2017 Health Care quality in vitro genetic toxicity data are for hormonal effects (81 FR 42912 at
Antiseptic final rule, we explained that available, a dermal study should not be 42930). As we explained in section
the MUsT paradigm has been used in necessary. The comment also contended IV.C.1., FDA has deferred further
the evaluation of topical dermatological rulemaking on alcohol, benzalkonium
that it is highly unlikely that the dermal

agents approved in the United States route of administration would result in chloride, and isopropyl alcohol to allow
since the early 1990s (82 FR 60474 at a higher systemic exposure than the oral for the development and submission to
60492 to 60493). It represents over 20 route of administration. the record of new safety and
years of interactions with multinational (Response 15) As we stated in the effectiveness data for these ingredients.
drug companies, during which time the 2016 Consumer Antiseptic Rub This includes the data necessary to
characterize isopropyl alcohol’s (Response 17) We understand that administration. Data on the potential for
potential for hormonal effects. animal use in tests for the efficacy and the active ingredient under study to
safety of human and animal products induce a neoplastic response in the skin
2. Animal Testing Issues
has been and continues to be a concern. with repeated dermal application are
(Comment 17) Comments argued that FDA is an active partner in efforts to necessary in order to assess the safety of
numerous scientific and regulatory reduce, refine, or replace (known as the alcohol, benzalkonium chloride, and
bodies have performed exposure-driven 3Rs) the use of animals in drug isopropyl alcohol for use in consumer
risk assessments of antiseptic products development (Ref. 12). In general, antiseptic rub products. If these data
and have not requested the types of however, there continues to be a need adequately confirm a lack of
animal and human study data that FDA for data from studies conducted in carcinogenicity potential in the skin
is requiring before making a finding that living, intact mammalian systems, when and, further, raise no concerns of any
such products are safe. Comments there are currently no viable and systemic targets of toxicity, and if an
asserted that under standard validated alternatives in place to adequately conducted MUsT
international practice, safety evaluations address the myriad questions inherent demonstrates low systemic
for antiseptic ingredients are based on to the drug safety assessment process bioavailability of the active ingredient,
conservative assumptions of exposure including determining the many then an oral carcinogenicity study, a
and potential differences between interrelated local and systemic fertility and early embryonic
species, rather than correlation of endpoints that are of concern in the development study, and a pre- and post-
findings from animal toxicity studies to overall safety assessment for an natal development study are unlikely to
humans based on kinetic information ingredient. The animal testing described be necessary to support a GRAS/GRAE
from both animals and humans. in the deferral letters for each of the determination, again unless an
One comment requested that FDA three deferred consumer antiseptic rub adequately conducted toxicology
expand its discussion of ways in which active ingredients was proposed in program reveals safety signals for a
animal use may be minimized and response to and in concurrence with particular active ingredient or for any
feature this discussion more NDAC guidance to generate the publicly known structurally similar compound.
prominently in rulemaking. These available data needed to fill identified Total animal usage would thereby be
include that efficacy testing take data gaps. The Agency remains open to reduced significantly.
precedence over safety testing, that considering data generated using non-
sharing of data be required, that route- 3. Bacterial Resistance Testing
animal methods.
to-route extrapolation be accepted for We emphasize that FDA does not (Comment 18) Comments relating to
carcinogenicity studies, and that data require that studies in animals be the issue of bacterial resistance were
from human-relevant, non-animal conducted before studies in humans. In submitted in response to the 2016
methods be accepted. This comment fact, until human MUsT data have been Consumer Antiseptic Rub proposed
stated that if FDA does not have a policy generated and evaluated, we will not rule. In general, the comments were
regarding the use of alternatives to have the evidence of systemic split with regard to whether antiseptics
animal testing, the Agency should bioavailability that would trigger the pose a public health risk from bacterial
thoroughly evaluate their applicability need for certain studies in animals. The resistance. Some comments agreed that
in each individual case. need for studies could also be triggered the pervasive use of consumer antiseptic
With regard to benzalkonium chloride by an adequately conducted toxicology rubs poses a risk for the development of
in particular, one comment argued that program that reveals a safety signal for bacterial resistance. Other comments
additional animal testing should not be the ingredient or for any known disagreed and criticized the data on
necessary unless the following structurally similar compound, and which they believe FDA based its
conditions are met: thereby, indicates the potential for concerns.
• Use of conservative approaches to adverse effects at exposure levels lower Specifically, comments dismissed the
calculate the margin of exposure is than those that result from maximal in vitro data cited by FDA in the
inadequate. usage. If data generated from safety or proposed rule as not reflecting real-life
• The margin of exposure justifies the efficacy testing in humans fail to meet conditions. The comments argued that
need for more data, but it is not possible the minimum criteria for a GRAS/GRAE the most useful assessment of the risk of
to generate the data by non-animal determination, it may not be necessary biocide resistance and cross-resistance
approaches, such as using PBPK to conduct animal studies including a to antibiotics are in-situ studies, studies
modeling, or through animal alternative dermal carcinogenicity study, an oral of clinical and environmental strains, or
test methods. carcinogenicity study, embryofetal biomonitoring studies. Some comments
• There is a perceived need for all development studies in rodents and asserted that studies of these types have
ingredients to have the same type of non-rodents, a fertility and early reinforced the idea that resistance and
information. embryonic development study, and a cross-resistance associated with
Another comment pointed to pre- and post-natal development study. antiseptics is a laboratory phenomenon
proprietary data cited by the With regard to the proposal to observed only when tests are conducted
Environmental Protection Agency and incorporate route-to-route extrapolation under unrealistic conditions. One
the Cosmetic Ingredient Review to in assessing potential carcinogenicity comment stated that there is little
support their findings that risk, for drug products whose primary credible evidence that antiseptic
benzalkonium chloride is safe for use in route of administration is via topical products play any role in antibiotic
disinfectants and cosmetics. The dermal application, a target tissue of resistance in human disease. The
Cosmetic Ingredient Review report concern is the skin and associated comment stated that, while some in
summarizes data from a tumorigenicity substructures. As we explained earlier, vitro lab studies have been successful in
study in mice and rabbits in which there are no validated methods forcing expression of resistance to
ulceration and inflammation, but no currently known to the Agency for antiseptic active ingredients in some
tumors, were observed. The comment predicting dermal carcinogenicity risk bacteria, real world data from
urged FDA to try to obtain these data to from data generated in studies that community studies using actual product
avoid duplicative testing. employed a non-dermal route of formulations show no correlation
between the use of such products and Studies performed using clinical (Comment 19) The comments also
antibiotic resistance. The comment isolates found strong evidence of addressed the data needed to assess the
stated that further evidence of real- antiseptic resistance to benzethonium risk of the development of resistance.
world data showing no antimicrobial and benzalkonium chloride (Refs. 27 to One comment disagreed with the
resistance development after the 35). Antiseptic resistance genes qacA/B proposed testing described in the 2016
continued use of consumer products and qacE (Ref. 32) were identified and, Consumer Antiseptic Rub proposed
containing antimicrobial active in 83 percent and 73 percent of the rule, arguing that there are no standard
compounds can be extracted from oral isolates tested, respectively, correlated laboratory methods for evaluating the
care clinical studies, which provide in with reduced susceptibility to development of antimicrobial
vivo data, under well-controlled benzalkonium and benzethonium resistance. With regard to the
conditions, on exposure to chloride. In contrast, two studies recommendation for mechanism
antimicrobial-containing formulations published by Kawamura-Sato et al. studies, they believed that it is unlikely
over prolonged periods of time (e.g., 6 (Refs. 36 and 37) found the MIC of that this kind of information can be
months to 5 years). The comment also benzalkonium chloride for 283 clinical developed for all active ingredients,
cited the conclusions of an International isolates to be well within in-use particularly given that the mechanism(s)
Conference on Antimicrobial Research concentration. of action may be concentration
held in 2012 on a possible connection Other studies examined a possible dependent and combination and
between biocide (antiseptic or correlation between antiseptic and formulation effects may be highly
disinfectant) resistance and antibiotic antibiotic resistance (Refs. 23 to 34 and relevant. The comments also argued that
resistance to support the point that there 37 to 46). Comparisons suggest that data characterizing the potential for
is no correlation between antiseptic use alterations in the mean susceptibility of transferring a resistance determinant to
and antibiotic resistance. Staphylococcus aureus to antimicrobial other bacteria is also an unrealistic
(Response 18) As explained in the biocides occurred between 1989 and requirement for a GRAS determination.
2016 Consumer Antiseptic Rub 2000, but these changes were mirrored Finally, a comment argued that the
proposed rule, we continue to believe in both methicillin resistant and requirements for data and information
that the development of bacteria that are susceptible S. aureus, suggesting that should be able to be satisfied through an
resistant to antibiotics is an important methicillin resistance had little to do ingredient-specific review of the
public health issue, and that additional with these changes (Ref. 46). In S. literature and without generation of new
data may tell us whether use of aureus, Escherichia coli, and laboratory data.
Pseudomonas aeruginosa, several (Response 19) In the 2016 Consumer
antiseptics in consumer settings may
correlations (both positive and negative) Antiseptic Rub proposed rule, we
contribute to the selection of bacteria
described the data needed to help
that are less susceptible to both between antibiotics and antimicrobial
establish a better understanding of the
antiseptics and antibiotics (81 FR 42912 biocides were found (Refs. 37, 39, 41,
interactions between antiseptic active
at 42926). Thus, we have conducted 44, 46, and 47). From the analyses of
ingredients used in consumer antiseptic
ingredient-specific reviews of the these clinical isolates, it is very difficult
rub products and bacterial resistance
literature pertaining to antiseptic to support a hypothesis that increased
mechanisms and the data needed to
resistance and antibiotic cross- biocide resistance is a cause of
provide the information necessary to
resistance, and determined that increased antibiotic resistance in these
perform an adequate risk assessment for
additional studies to assess the species.
these consumer antiseptic rub products.
development of cross-resistance to Bacteria expressing resistance We suggested a tiered approach as an
antibiotics are needed for only one of mechanisms with a decreased efficient means of developing data to
the deferred active ingredients, susceptibility to antiseptics and some address this resistance issue, beginning
benzalkonium chloride. In the case of antibiotics have been isolated from a with laboratory studies in conjunction
ethyl alcohol and isopropyl alcohol, variety of natural settings (Refs. 48 and with a literature review aimed at
sufficient data have been provided to 49). Although the prevalence of evaluating the impact of exposure to
assess the risk of antiseptic resistance antiseptic tolerant subpopulations in nonlethal amounts of antiseptic active
and antibiotic cross-resistance. natural microbial populations is ingredients on antiseptic and antibiotic
Laboratory studies have identified currently low, overuse of antiseptic bacterial susceptibilities, along with
and characterized bacterial resistance active ingredients has the potential to additional data, if necessary, to help
mechanisms that confer a reduced select for resistant microorganisms. assess the likelihood that changes in
susceptibility to antiseptics and, in In sum, adequate data do not exist susceptibility observed in the
some cases, antibiotics. Specifically, currently to determine whether the preliminary studies would occur in the
these data suggest that resistance development of bacterial antiseptic consumer setting (81 FR 42912 at 42926
development in the laboratory is very resistance could also select for antibiotic to 42927). As we explained in the 2016
common for some active ingredients, resistant bacteria or how significant this Consumer Antiseptic Rub proposed
such as benzethonium and selective pressure would be relative to rule, we recognize that the science of
benzalkonium chloride (Refs. 13 to 17), the overuse of antibiotics, an important evaluating the potential of compounds
and chloroxylenol, used in topical driver for antibiotic resistance. to cause bacterial resistance is evolving
antiseptic products (Refs. 18 to 23). In Moreover, the possible correlation and acknowledged the possibility that
contrast, resistance to other active between antiseptic and antibiotic alternative data may be identified as an
ingredients, such as povidone-iodine resistance is not the only concern. appropriate substitute for evaluating the
(Refs. 24 to 26) occurs infrequently in Reduced antiseptic susceptibility may development of resistance (81 FR 42912
the laboratory setting. We acknowledge allow the persistence of organisms in
at 42927).
that observations made in the laboratory the presence of low-level residues and For benzalkonium chloride, for which
setting are not necessarily replicated in contribute to the survival of antibiotic resistance testing is necessary as
the real-world setting. Therefore, we resistant organisms. Data are not described in the applicable deferral
assessed additional studies performed currently available to assess the letter, we have advised manufacturers,
in the clinical setting. magnitude of this risk. as an initial step, to conduct an active
ingredient-specific literature review monograph for that active ingredient. As VII. Economic Analysis of Impacts
related to antiseptic resistance and the comment suggests, we may consider
A. Introduction
antibiotic cross-resistance to assess the at that time whether the labeling for
active ingredient’s effect on consumer antiseptic rub products We have examined the impacts of the
development of cross-resistance to containing alcohol should contain document under Executive Order 12866,
antiseptics and antibiotics in the additional directions or warnings aimed Executive Order 13563, Executive Order
consumer setting, and to submit as at reducing the risk of ingestion by 13771, the Regulatory Flexibility Act (5
much information and data as can be U.S.C. 601–612), and the Unfunded
young children. We may also consider
provided (Ref. 50). If the literature Mandates Reform Act of 1995 (Pub. L.
whether using hand sanitizing wipes or 104–4). Executive Orders 12866 and
review results show evidence of
products that do not contain alcohol 13563 direct us to assess all costs and
antiseptic or antibiotic resistance,
could reduce the risk of ingestion and benefits of available regulatory
additional studies may be necessary,
consistent with the recommendations poisoning and, if so, whether and how alternatives and, when regulation is
outlined in the 2016 Consumer that information should be incorporated necessary, to select regulatory
Antiseptic Rub proposed rule, to help into labeling. approaches that maximize net benefits
assess the impact of the active E. Comments on the Preliminary (including potential economic,
ingredient on antiseptic and antibiotic environmental, public health and safety,
Regulatory Impact Analysis and FDA
susceptibilities. If, however, the and other advantages; distributive
Response
literature review provides no evidence impacts; and equity). Executive Order
that the active ingredient affects (Comment 21) One comment raised 13771 requires that the costs associated
antiseptic or antibiotic susceptibility, issues concerning the preliminary with significant new regulations ‘‘shall,
then it is likely that no further studies regulatory impact analysis (RIA) and the to the extent permitted by law, be offset
to address development of resistance Agency’s assessment of the net benefit by the elimination of existing costs
will be needed to support a GRAS of the rulemaking. The comment stated associated with at least two prior
determination. regulations.’’ This final rule is a
that FDA’s RIA did not account for all
significant regulatory action as defined
4. The Risk of Ingestion and Poisoning the costs and overestimated the benefits by Executive Order 12866.
(Comment 20) Comments raised associated with the proposed regulation. The Regulatory Flexibility Act
concerns about the risks of poisoning The comment noted that if the active requires us to analyze regulatory options
from consumer antiseptic rubs ingredients in consumer antiseptic rub that would minimize any significant
containing alcohol and, in particular, products are safe, there is no benefit to impact of a rule on small entities.
about the risk of ingestion of these avoiding exposure to them. In addition, Although the additional costs this
products by young children. A comment there are costs associated with the loss document imposes on small entities are
recommended that, if consumer of availability of hand rub antiseptics in small, the consumer antiseptic rub
antiseptic rubs are used in schools, that consumer settings. product industry is mainly composed of
teachers store them in a safe place and (Response 21) Our response is establishments with 500 or fewer
that students only use them with adult provided in the full discussion of employees. Therefore, we find that the
supervision. The comment also economic impacts, available in the document will have a significant
recommended using hand sanitizing economic impact on a substantial
docket for this document (Docket No.
wipes or products that do not contain number of small entities. We have
FDA–2016–N–0124, (Ref. 51), https://
alcohol to reduce the risk of ingestion analyzed various regulatory options to
and poisoning. www.regulations.gov) and at https://
examine the impact on small entities.
(Response 20) We agree that hand www.fda.gov/AboutFDA/Reports The Unfunded Mandates Reform Act
sanitizers or antiseptic wipes should be ManualsForms/Reports/ of 1995 (section 202(a)) requires us to
stored out of the reach of children and EconomicAnalyses/default.htm. prepare a written statement, which
should be used with adult supervision. VI. Effective Date includes an assessment of anticipated
We note that the labeling for all drugs costs and benefits, before issuing ‘‘any
marketed under an OTC monograph is In the 2016 Consumer Antiseptic Rub rule that includes any Federal mandate
required to contain the general warning proposed rule, we recognized, based on that may result in the expenditure by
‘‘Keep out of reach of children’’ in bold the scope of products subject to this State, local, and tribal governments, in
type (21 CFR 330.1(g)). As we explained final rule, that manufacturers would the aggregate, or by the private sector, of
in the 2016 Consumer Antiseptic Rub need time to comply with this final rule. $100,000,000 or more (adjusted
proposed rule, however, the labeling for Thus, as proposed in the 2016 annually for inflation) in any one year.’’
consumer antiseptic rub products Consumer Antiseptic Rub proposed rule The current threshold after adjustment
containing a particular active ingredient for inflation is $154 million, using the
(81 FR 42912 at 42930 to 42931), this
will be addressed as part of the final most current (2018) Implicit Price
document will be effective 1 year after
rule if FDA makes a determination that Deflator for the Gross Domestic Product.
the active ingredient is GRAS/GRAE (81 the date of the document’s publication
in the Federal Register. On or after that This document would not result in an
FR 42912 at 42913). Because all three of expenditure in any year that meets or
the ingredients that are eligible for date, any OTC consumer antiseptic rub
exceeds this amount.
consideration as a consumer antiseptic drug products containing an ingredient
rub, including alcohol, have been that we have found in this document to B. Summary of Costs and Benefits
granted deferrals, and FDA has not yet be ineligible for consideration under the As discussed in the preamble, this
made a GRAS/GRAE determination for OTC Drug Review for the OTC document applies to active ingredients
these active ingredients, we do not consumer antiseptic rub monograph used in OTC consumer antiseptic rub
address their labeling in this document. cannot be introduced or delivered for products, including hand ‘‘sanitizers’’
If alcohol and/or isopropyl alcohol are introduction into interstate commerce and consumer antiseptic wipes. Here,
subsequently found to be GRAS/GRAE, unless it is the subject of an approved we refer to consumer antiseptic rubs or
we will address its labeling in the final NDA or ANDA. consumer rubs as those products that
are intended to be used when soap and rub products with ineligible active document are estimated to be between
water are not available and are not ingredients will either reformulate and $0.13 million and $0.29 million per
intended to be rinsed off with water. An relabel their products to include the year; the corresponding estimated cost
OTC drug is covered by the OTC Drug three deferred active ingredients which at a discount rate of 7 percent is
Review if its conditions of use existed are eligible for consideration under the between $0.15 million and $0.36
in the OTC drug marketplace on or OTC Drug Review, discontinue million per year.
before May 11, 1972 (37 FR 9464). The production of their consumer antiseptic A potential benefit of this document
only active ingredients eligible for rub products, or reformulate their is that the removal of potentially
evaluation under the OTC Drug Review products as antiseptic-free topical harmful antiseptic active ingredients in
for use in OTC consumer antiseptic rub cleansers or wipes. In table 4, we consumer antiseptic rub products may
products are ethyl alcohol (referred to provide a summary of the estimated prevent health consequences associated
subsequently as alcohol), isopropyl costs of the document that involve with exposure to such active
alcohol, and benzalkonium chloride. In product reformulation and relabeling of ingredients. FDA lacks the necessary
response to requests submitted to the consumer rub products that contain information to estimate the impact of
2016 Consumer Antiseptic Rub PR, FDA active ingredients that are ineligible for exposure to antiseptic active ingredients
has deferred regulatory action on these consideration under the OTC Drug in consumer antiseptic rub products on
active ingredients. Accordingly, FDA Review for use in consumer rubs. human health outcomes. We are,
does not make a GRAS/GRAE Manufacturers of consumer antiseptic however, able to estimate the reduction
determination regarding these three rub products that contain the deferred in the aggregate exposure to antiseptic
active ingredients in this document. The active ingredients may also incur active ingredients found in currently
monograph or non-monograph status of additional costs associated with the marketed consumer antiseptic rub
these three active ingredients will be necessary safety and effectiveness products. The document will lead to an
addressed, either after completion and testing required to demonstrate that the estimated reduction in aggregate
analysis of studies to address the safety deferred active ingredient is GRAS/ exposure to benzethonium chloride that
and effectiveness data gaps of these GRAE. However, these testing costs are ranges from 110 pounds to 254 pounds
active ingredients or at a later date, if not included in the regulatory impact per year. This document may also result
these studies are not completed. analysis for this document because this in reduced exposure to other ineligible
This document establishes that all document does not require any testing. active ingredients. However, FDA can
other consumer antiseptic rub active Although the testing costs are not only estimate the reduced exposure to
ingredients are not eligible for attributable to this document, we benzethonium chloride at this time.
consideration under the OTC Drug estimate and present these costs Furthermore, we are unable to translate
Review for use in consumer antiseptic separately in the RIA analysis. the aggregate exposure to benzethonium
rub products. Drug products containing We estimate that the present value of chloride into monetized benefits at this
the 28 ineligible active ingredients the one-time costs associated with time because we lack information on the
identified in the 2016 Consumer compliance range from $1.07 million to change in the short- and long-term
Antiseptic Rub PR will require approval $2.50 million with a primary estimate of health risks associated with a 1-pound
under an NDA or ANDA prior to $1.87 million. Annualizing upfront increase in exposure to each antiseptic
marketing. However, we expect that costs over a 10-year period at a discount active ingredient in consumer antiseptic
manufacturers of consumer antiseptic rate of 3 percent, the costs of this rub products.
TABLE 4—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF DOCUMENT

Units
Primary Low High Notes
Category Discount Period
estimate estimate estimate Year (years)
rate covered
dollars (percent) (years)
Benefits:
Annualized ....................... .................. .................. .................. .................. 7 10
Monetized $millions/year .................. .................. .................. .................. 3 10
Annualized ....................... 182 110 254 .................. 7 10 Values represent pounds of
reduced annual exposure to
ineligible active ingredients.
Quantified ......................... 182 110 254 .................. 3 10 Values represent pounds of
reduced annual exposure to
ineligible active ingredients.
Qualitative ........................ .................. .................. .................. .................. .................. ..................
Costs:
Annualized ....................... $0.27 $0.15 $0.36 2017 7 10
Monetized $millions/year 0.22 0.13 0.29 2017 3 10
Annualized ....................... .................. .................. .................. .................. 7 ..................
Quantified ......................... .................. .................. .................. .................. 3 ..................
Qualitative ........................ .................. .................. .................. .................. .................. ..................
Transfers:
Federal ............................. .................. .................. .................. .................. 7 ..................
Annualized ....................... .................. .................. .................. .................. 3 ..................
Monetized $millions/year .................. .................. .................. .................. .................. ..................
TABLE 4—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF DOCUMENT—Continued

Units
Primary Low High Notes
Category Discount Period
estimate estimate estimate Year (years)
rate covered
dollars (percent) (years)
From/To ........................... From: To:
Other ................................ .................. .................. .................. .................. 7 10

Annualized ....................... .................. .................. .................. .................. 3 10
Monetized $millions/year .................. .................. .................. .................. .................. ..................
From/To ........................... From: To:
Effects:
State, Local or Tribal
Government: none.
Small Business:
Wages:
Growth:
In line with Executive Order 13771, in savings over an infinite time horizon. would be considered a regulatory action
table 5 we estimate present and Based on these costs this document under Executive Order 13771.
annualized values of costs and cost
TABLE 5—EXECUTIVE ORDER 13771 SUMMARY TABLE

[In $ millions 2016 dollars, over an infinite time horizon]
Primary Lower Upper Primary Lower Upper

Item estimate estimate estimate estimate estimate estimate
(7%) (7%) (7%) (3%) (3%) (3%)
Present Value of Costs .................................................... $1.77 $1.02 $2.37 $1.77 $1.02 $2.37
Present Value of Cost Savings ........................................ 0.00 0.00 0.00 0.00 0.00 0.00
Present Value of Net Costs ............................................. 1.77 1.02 2.37 1.77 1.02 2.37
Annualized Costs ............................................................. 0.12 0.07 0.17 0.05 0.03 0.07
Annualized Cost Savings ................................................. 0.00 0.00 0.00 0.00 0.00 .00
Annualized Net Costs ...................................................... 0.12 0.07 0.17 0.05 0.03 0.07
C. Summary of Regulatory Flexibility VIII. Paperwork Reduction Act of 1995 responsibilities between the Federal
Analysis Government and Indian Tribes.
This document contains no collection
Accordingly, we conclude that the
The Regulatory Flexibility Act of information. Therefore, clearance by
document does not contain policies that
requires Agencies to analyze regulatory the Office of Management and Budget
(OMB) under the Paperwork Reduction have tribal implications as defined in
options that would minimize any the Executive Order and, consequently,
significant impact of a rule on small Act of 1995 is not required.
a tribal summary impact statement is
entities. Because many small entities IX. Analysis of Environmental Impact not required.
produce consumer antiseptic rub
We have determined under 21 CFR XI. Federalism
products, we find that the document
25.31(a) that this action is of a type that
will have a significant economic impact does not individually or cumulatively We have analyzed this document in
on a substantial number of small have a significant effect on the human accordance with the principles set forth
entities. The Final Regulatory Flexibility environment. Therefore, neither an in Executive Order 13132. Section 4(a)
Analysis, as required under the environmental assessment nor an of the Executive order requires agencies
Regulatory Flexibility Act, can be found environmental impact statement is to ‘‘construe . . . a Federal statute to
in the Regulatory Impact Analysis required. preempt State law only where the
discussed below. statute contains an express preemption
X. Consultation and Coordination With
We have developed a comprehensive provision or there is some other clear
Indian Tribal Governments
Regulatory Impact Analysis that evidence that the Congress intended
assesses the impacts of the document. We have analyzed this document in preemption of State law, or where the
The full analysis of economic impacts is accordance with the principles set forth exercise of State authority conflicts with
available in Docket No. FDA–2016–N– in Executive Order 13175. We have the exercise of Federal authority under
determined that the document does not the Federal statute.’’ The sole statutory
0124 (Ref. 51) and at https://

www.fda.gov/AboutFDA/Reports contain policies that have substantial provision giving preemptive effect to the
ManualsForms/Reports/Economic direct effects on one or more Indian document is section 751 of the FD&C
Tribes, on the relationship between the Act (21 U.S.C. 379r). We have complied
Analyses/default.htm.
Federal Government and Indian Tribes, with all of the applicable requirements
or on the distribution of power and under the Executive order and have
determined that the preemptive effects Cutaneous Absorption of Various against Vancomycin-Resistant
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Antiseptic Rub FDA Final Rule Making

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Federal Register / Vol. 84, No.

71 / Friday, April 12, 2019 / Rules and Regulations 14847

Abbreviation What it means

ANDA .................................. Abbreviated New Drug Application.

ATCC .................................. American Type Culture Collection.

Abbreviation What it means

GRAS/GRAE ...................... Generally Recognized as Safe/Generally Recognized as Effective.

TABLE 2—PUBLIC MEETINGS RELEVANT TO CONSUMER ANTISEPTIC RUBS—Continued

Alcohol 60 to 95 percent ......................................................................................................................................... I 2 .................... IIISE 3.

non-inferiority and superiority after

Assessment of Antimicrobial Activity D. Comments on Safety and FDA

that it is highly unlikely that the dermal

TABLE 4—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF DOCUMENT

TABLE 4—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF DOCUMENT—Continued

From/To ........................... From: To:

Other ................................ .................. .................. .................. .................. 7 10

From/To ........................... From: To:

TABLE 5—EXECUTIVE ORDER 13771 SUMMARY TABLE

Primary Lower Upper Primary Lower Upper

0124 (Ref. 51) and at https://

www.fda.gov/Drugs/DrugSafety/ Epidemiology, 29(8):736–741, 2008. www.ncbi.nlm.nih.gov/pubmed/2866

?term=19762119. coli Isolates on Antibiotic

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