[Federal Register Volume 84, Number 71 (Friday, April 12, 2019)]
[Rules and Regulations]
[Pages 14847-14864]
[FR Doc No: 2019-06791]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2016-N-0124 (formerly part of Docket No. FDA-1975-N-
0012)]
RIN 0910-AH97

Safety and Effectiveness of Consumer Antiseptic Rubs; Topical
Antimicrobial Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; finding of ineligibility for inclusion in final
monograph.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing this final action establishing that certain active ingredients
used in nonprescription (also known as over-the-counter (OTC)) consumer
antiseptic products intended for use without water (referred to
throughout as consumer antiseptic rubs or consumer rubs) are not
eligible for evaluation under the OTC Drug Review for use in consumer
antiseptic rubs. Drug products containing these ineligible active
ingredients will require approval under a new drug application (NDA) or
abbreviated new drug application (ANDA) prior to marketing. FDA is
issuing this final action after considering the recommendations of the
Nonprescription Drugs Advisory Committee (NDAC), public comments on the
Agency's notices of proposed rulemaking, and all data and information
on OTC consumer antiseptic rub products that have come to the Agency's
attention. This final action finalizes the 1994 tentative final
monograph (TFM) for OTC consumer antiseptic rub drug products that
published in the Federal Register of June 17, 1994 (the 1994 TFM), as
amended by the proposed rule published in the Federal Register (FR) of
June 30, 2016 (2016 Consumer Antiseptic Rub proposed rule).

DATES: Effective April 13, 2020.

ADDRESSES: For access to the docket to read background documents or
comments received, go to https://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule, into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Anita Kumar, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5445, Silver Spring, MD 20993-0002, 301-
796-1032.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics and Scope of Document
IV. Background
    A. Significant Rulemakings Relevant to This Document
    B. Public Meetings Relevant to This Document
    C. Eligibility for the OTC Drug Review
    D. Updated Statistical Analysis for Efficacy
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. General Comments on the Proposed Rule and FDA Response
    C. Comments on Effectiveness and FDA Response
    D. Comments on Safety and FDA Response
    E. Comments on the Preliminary Regulatory Impact Analysis and
FDA Response
VI. Effective Date
VII. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
    C. Summary of Regulatory Flexibility Analysis
VIII. Paperwork Reduction Act of 1995
IX. Analysis of Environmental Impact
X. Consultation and Coordination With Indian Tribal Governments
XI. Federalism
XII. References

I. Executive Summary

A. Purpose of the Final Rule

    This document finalizes the 2016 Consumer Antiseptic Rub proposed
rule. This final rule applies to active ingredients used in consumer
antiseptic rub products that are sometimes referred to as rubs, leave-
on products, or hand ``sanitizers,'' as well as to consumer antiseptic
wipes. These products are intended to be used when soap and water are
not available and are left on and not rinsed off with water. We will
refer to them here as consumer antiseptic rubs or consumer rubs.
    In response to several requests submitted to the 2016 Consumer
Antiseptic Rub proposed rule, FDA has deferred further rulemaking on
three active ingredients used in OTC consumer antiseptic rub products
to allow for the development and submission to the record of new safety
and effectiveness data for these ingredients. The deferred active
ingredients are benzalkonium chloride, alcohol (also referred to as
ethanol or ethyl alcohol), and isopropyl alcohol. Accordingly, FDA does
not make a generally recognized as safe and effective (GRAS/GRAE)
determination in this document for these three active ingredients for
use in OTC consumer antiseptic rubs. The monograph or non-monograph
status of these three ingredients will be addressed, either after
completion and analysis of studies to address the safety and
effectiveness data gaps of these ingredients or at another time, if
these studies are not completed. As discussed below, this document
describes the studies necessary as a scientific matter for the Agency
to determine whether an active ingredient is GRAS/GRAE for use in
consumer rubs.
    The three deferred active ingredients--benzalkonium chloride, ethyl
alcohol, and isopropyl alcohol--are the only active ingredients
determined to be eligible for evaluation under the OTC Drug Review for
use in OTC consumer antiseptic rub products. With respect to the 28
ineligible active ingredients identified in the 2016 Consumer
Antiseptic Rub proposed rule, we have not received any new information
since the publication of the 2016 Consumer Antiseptic Rub proposed rule
demonstrating that the active ingredients we previously proposed to be
ineligible should be considered eligible for evaluation under the OTC
Drug Review for inclusion in the OTC consumer antiseptic rub monograph.
Accordingly, consumer antiseptic rub drug products containing any of
these ineligible active ingredients require approval under an NDA or
ANDA prior to marketing.
    This document covers only OTC consumer antiseptic rubs that are
intended for use without water. This document does not cover consumer
antiseptic washes (78 FR 76444, 81 FR 61106); healthcare antiseptics
(80 FR 25166, 82 FR 60474); antiseptics identified as ``first aid
antiseptics'' in the 1991 First Aid tentative final monograph (TFM) (56
FR 33644); or antiseptics used by the food industry.

B. Summary of the Major Provisions of the Final Rule

    This document finalizes the ineligibility status of the 28 active
ingredients listed in section IV.C.2. No additional information was
submitted demonstrating that any of the 28 ineligible active
ingredients identified in the 2016 Consumer Antiseptic Rub proposed
rule are eligible for evaluation under the OTC Drug Review for use in
an OTC consumer antiseptic rub, and thus, these ineligible ingredients
are not included in the OTC Consumer Antiseptic Rub monograph at this
time. OTC consumer antiseptic rub products containing these ineligible
ingredients are new drugs for which approved NDAs or ANDAs are required
prior to marketing.
    Requests were made that benzalkonium chloride, ethyl alcohol, and
isopropyl alcohol be deferred from consideration in this consumer
antiseptic rub document to allow more time for interested parties to
complete necessary studies to fill the safety and effectiveness data
gaps identified in the 2016 Consumer Antiseptic Rub proposed rule for
these ingredients. In October 2017, we agreed to defer rulemaking on
these three ingredients (see Docket No. FDA-2016-N-0124 at https://www.regulations.gov and also https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm538131.htm).

C. Costs and Benefits

    This document defers regulatory action for three consumer
antiseptic rub active ingredients (ethyl alcohol, isopropyl alcohol,
and benzalkonium chloride) that are eligible for evaluation under the
OTC Drug Review for use in OTC consumer antiseptic rub products, while
establishing that all other consumer rub active ingredients are
ineligible for evaluation under the OTC Drug Review and OTC consumer
antiseptic rubs containing these ineligible active ingredients require
approval under an NDA or ANDA prior to marketing. The costs of this
document are associated with the reformulation and relabeling of
consumer rub products that currently contain ineligible active
ingredients. The benefits of this document include consumers' reduced
exposure to potentially unsafe consumer antiseptic rub products, as
well as avoiding the deadweight loss associated with reduced
consumption of ineffective products. FDA is only able to monetize the
costs of this document. We estimate that the present value of the one-
time costs associated with compliance range from $1.07 million to $2.50
million with a primary estimate of $1.87 million. Annualizing upfront
costs over a 10-year period at a discount rate of 3 percent, the costs
of this document are estimated to be between $0.13 million and $0.29
million per year; the corresponding estimated cost at a discount rate
of 7 percent is between $0.15 million and $0.36 million per year.
    The full discussion of economic impacts is available in Docket No.
FDA-2016-N-0124 and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

II. Table of Abbreviations/Commonly 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.

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.
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III. Introduction

    In the following sections, we provide a brief description of
terminology used in the OTC Drug Review regulations, an overview of OTC
topical antiseptic drug products, and a more detailed description of
the OTC consumer antiseptic rub active ingredients that are the subject
of this document.

A. Terminology Used in the OTC Drug Review Regulations

1. Proposed, Tentative Final, and Final Monographs
    To conform to terminology used in the OTC Drug Review regulations
(Sec.  330.10 (21 CFR 330.10)), the advanced notice of proposed
rulemaking (ANPR) that was published in the Federal Register of
September 13, 1974 (39 FR 33103) (1974 ANPR), was designated as a
``proposed monograph.'' Similarly, the notices of proposed rulemaking,
which were published in the Federal Register of January 6, 1978 (43 FR
1210) (1978 TFM); the Federal Register of June 17, 1994 (59 FR 31402)
(1994 TFM); the Federal Register of December 17, 2013 (78 FR 76444)
(2013 Consumer Antiseptic Wash proposed rule); the Federal Register of
May 1, 2015 (80 FR 25166) (2015 Health Care Antiseptic proposed rule);
and the Federal Register of June 30, 2016 (81 FR 42912) (2016 Consumer
Antiseptic Rub proposed rule) were each designated as a TFM (see table
1 in section IV.A.).
2. Category I, II, and III Classifications
    The OTC drug regulations in Sec.  330.10 use the terms ``Category
I'' (generally recognized as safe and effective and not misbranded),
``Category II'' (not generally recognized as safe and effective or
misbranded), and ``Category III'' (available data are insufficient to
classify as generally recognized as safe and effective, and further
testing is necessary). Section 330.10 provides that any testing
necessary to resolve the safety or effectiveness issues that resulted
in an initial Category III classification, and submission to FDA of the
results of that testing or any other data, must be done during the OTC
drug rulemaking process before the establishment of a final monograph
(i.e., a final rule or regulation). Therefore, the proposed rules (at
the tentative final monograph stage) used the concepts of Categories I,
II, and III. At the final monograph stage, FDA does not use the terms
``Category I,'' ``Category II,'' and ``Category III.'' Instead, the
term ``monograph conditions'' is used in place of Category I, and
``nonmonograph conditions'' is used in place of Categories II and III.

B. Topical Antiseptics and Scope of Document

    The OTC topical antimicrobial rulemaking encompasses a range of
drug products that contain a number of active ingredients and are
labeled and marketed for a variety of intended uses. The 1974 ANPR for
topical antimicrobial products encompassed products for both healthcare
and consumer use (39 FR 33103). The 1974 ANPR covered seven different
intended uses for these products: (1) Antimicrobial soap; (2)
healthcare personnel hand wash; (3) patient preoperative skin
preparation; (4) skin antiseptic; (5) skin wound cleanser; (6) skin
wound protectant; and (7) surgical hand scrub (39 FR 33103 at 33140).
FDA subsequently identified skin antiseptics, skin wound cleansers, and
skin wound protectants as antiseptics used primarily by consumers for
first aid use and referred to them collectively as ``first aid
antiseptic drug products.'' We published a separate TFM covering first
aid antiseptics in the Federal Register of July 22, 1991 (56 FR 33644).
We do not discuss first aid antiseptics further in this document, and
this document does not address the status of first aid antiseptics.
    The four remaining categories of topical antimicrobials were
addressed in the 1994 TFM (59 FR 31402). The 1994 TFM covered: (1)
Antiseptic hand wash (i.e., consumer hand wash); (2) healthcare
personnel hand wash; (3) patient preoperative skin preparation; and (4)
surgical hand scrub (59 FR 31402 at 31442). In the 1994 TFM, FDA also
identified a new category of antiseptics for use by the food industry
and requested relevant data and information (59 FR 31402 at 31440). We
do not discuss food handler antiseptics further in this document, and
this document does not address the status of antiseptics for food
industry use.
    The 1994 TFM did not distinguish between consumer antiseptic washes
and rubs and healthcare antiseptic washes and rubs. In the 2013
Consumer Antiseptic Wash proposed rule, we proposed that our evaluation
of OTC antiseptic drug products be further subdivided into healthcare
antiseptics and consumer antiseptics (78 FR 76444 at 76446). These
categories are distinct based on the proposed use setting, target
population, and the fact that each setting presents a different level
of risk for infection. In the 2013 Consumer Antiseptic Wash proposed
rule (78 FR 76444 at 76446 to 76447) and the 2016 Consumer Antiseptic
Rub proposed rule (81 FR 42912 at 42915 to 42916), we proposed that our
evaluation of OTC consumer antiseptic drug products be further
subdivided into consumer washes (products that are rinsed off with
water, including hand washes and body washes) and consumer rubs
(products that are not rinsed off after use, including hand rubs and
antibacterial wipes). This document does not address the status of OTC
consumer antiseptic wash or healthcare antiseptic products.
    This document covers only OTC consumer antiseptic rubs. Completion
of the monograph for consumer antiseptic rubs and certain other
monographs for the active ingredient triclosan are subject to a Consent
Decree entered by the U.S. District Court for the Southern District of
New York on November 21, 2013, in Natural Resources Defense Council,
Inc. v. United States Food and

Drug Administration, et al., 10 Civ. 5690 (S.D.N.Y.).

IV. Background

    In this section, we describe the significant rulemakings and public
meetings relevant to this document and discuss our response to comments
received on the 2016 Consumer Antiseptic Rub proposed rule.

A. Significant Rulemakings Relevant to This Document

    A summary of the significant Federal Register publications relevant
to this document is provided in table 1. Other publications relevant to
this document are available at https://www.regulations.gov in FDA
Docket No. 1975-N-0012 (formerly Docket No. 1975-N-0183H and Docket No.
FDA-2015-N-0101).

    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
 1974, 39 FR 33103).            monograph for OTC topical antimicrobial
                                drug products, together with the
                                recommendations of the advisory review
                                panel (the Panel) responsible for
                                evaluating data on the active
                                ingredients in this drug class.
1978 Antimicrobial TFM         We published our tentative conclusions
 (January 6, 1978, 43 FR        and proposed effectiveness testing for
 1210).                         the drug product categories evaluated by
                                the Panel, reflecting our evaluation of
                                the Panel's recommendations and comments
                                and data submitted in response to the
                                Panel's recommendations.
1991 First Aid TFM (July 22,   We amended the 1978 TFM to establish a
 1991, 56 FR 33644).            separate monograph for OTC first aid
                                antiseptic products. In the 1991 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
 TFM (June 17, 1994, 59 FR      separate monograph for the group of
 31402).                        products referred to as OTC topical
                                healthcare antiseptic drug products.
                                These antiseptics are generally intended
                                for use by healthcare professionals.
                               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 consumer use:
                                Antiseptic hand wash.
2013 Consumer Antiseptic Wash  We issued a proposed rule to amend the
 TFM (December 17, 2013, 78     1994 TFM and to establish data standards
 FR 76444).                     for determining whether OTC consumer
                                antiseptic washes are GRAS/GRAE.
                               In the 2013 Consumer Antiseptic Wash TFM,
                                we proposed that additional safety and
                                effectiveness data are necessary to
                                support the safety and effectiveness of
                                consumer antiseptic wash active
                                ingredients.
2015 Health Care Antiseptic    We issued a proposed rule to amend the
 TFM (May 1, 2015, 80 FR        1994 TFM and to establish data standards
 25166).                        for determining whether OTC healthcare
                                antiseptics are GRAS/GRAE.
                               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 Rub   We issued a proposed rule to amend the
 TFM (June 30, 2016, 81 FR      1994 TFM and to establish data standards
 42912).                        for determining whether OTC consumer
                                antiseptic rubs are GRAS/GRAE.
                               In the 2016 Consumer Antiseptic Rub TFM,
                                we proposed that additional safety and
                                effectiveness data are necessary to
                                support the safety and effectiveness of
                                consumer antiseptic rub active
                                ingredients.
2016 Consumer Antiseptic Wash  We issued a final rule finding that
 Final Monograph (September     certain active ingredients used in OTC
 6, 2016, 81 FR 61106).         consumer antiseptic wash products are
                                not GRAS/GRAE.
                               We deferred further rulemaking on three
                                specific active ingredients
                                (benzalkonium chloride, benzethonium
                                chloride, and chloroxylenol) used in OTC
                                consumer antiseptic wash products to
                                allow for the development and submission
                                of new safety and effectiveness data to
                                the record for those ingredients.
2017 Health Care Antiseptic    We issued a final rule finding that
 Final Monograph (December      certain active ingredients used in OTC
 20, 2017, 82 FR 60474).        healthcare antiseptic products are not
                                GRAS/GRAE.
                               We deferred further rulemaking on six
                                specific active ingredients
                                (benzalkonium chloride, benzethonium
                                chloride, 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 ingredients.
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\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 Document

    In addition to the Federal Register publications listed in table 1,
there have been four meetings of the NDAC that are relevant to the
discussion of OTC consumer antiseptic rubs' safety and effectiveness.
These meetings are summarized in table 2.

      Table 2--Public Meetings Relevant to Consumer Antiseptic Rubs
------------------------------------------------------------------------
        Date and type of meeting               Topic of discussion
------------------------------------------------------------------------
January 1997; NDAC Meeting (Joint        Antiseptic and antibiotic
 meeting with the Anti-Infective Drugs    resistance in relation to an
 Advisory Committee) (January 6, 1997,    industry proposal for consumer
 62 FR 764).                              and healthcare antiseptic
                                          effectiveness testing (Health
                                          Care Continuum Model) (Refs. 1
                                          and 2).
March 2005; NDAC Meeting (February 18,   The use of surrogate endpoints
 2005, 70 FR 8376).                       and study design issues for
                                          the in vivo testing of
                                          healthcare antiseptics (Ref.
                                          3).

October 2005; NDAC Meeting (September    Benefits and risks of consumer
 15, 2005, 70 FR 54560).                  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,   Safety testing framework for
 2014, 79 FR 44042).                      healthcare antiseptic active
                                          ingredients (Ref. 6).
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C. Eligibility for the OTC Drug Review

    An OTC drug is covered by the OTC Drug Review if its conditions of
use existed in the OTC drug marketplace on or before May 11, 1972 (37
FR 9464).\1\ Conditions of use include, among other things, active
ingredient, dosage form and strength, route of administration, and
specific OTC use or indication of the product (see 21 CFR 330.14(a)).
To determine eligibility for the OTC Drug Review, FDA typically must
have actual product labeling or a facsimile of labeling that documents
the conditions of marketing of a product before May 1972 (see Sec.
330.10(a)(2)). FDA considers a drug that is ineligible for inclusion in
the OTC monograph system to be a new drug that requires FDA approval of
an NDA or ANDA prior to marketing. The ineligibility of an active
ingredient for evaluation under the OTC Drug Review for use in an OTC
consumer antiseptic rub does not affect eligibility of that active
ingredient under any other OTC drug monograph.
---------------------------------------------------------------------------

    \1\ Also, note that drugs initially marketed in the United
States after the OTC Drug Review began in 1972 and drugs without any
U.S. marketing experience can be considered under the OTC Drug
Review based on submission of a time and extent application. (See 21
CFR 330.14.)
---------------------------------------------------------------------------

1. Eligible Active Ingredients
    Table 3 lists the active ingredients eligible for evaluation under
the OTC Drug Review for use in OTC consumer antiseptic rubs and
provides the classification proposed in the 1994 TFM and the
classification proposed in the 2016 Consumer Antiseptic Rub proposed
rule.

      Table 3--Classification of OTC Consumer Antiseptic Rub Active
        Ingredients in the 1994 TFM and in the 2016 Proposed Rule
------------------------------------------------------------------------
                                 1994 TFM proposal
       Active ingredient                \1\           2016 Proposed rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent......  I \2\..............  IIISE \3\.
Isopropyl alcohol 70 to 91.3    IIIE...............  IIISE.
 percent.
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
  antiseptic 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 proposed to be classified as Category
I, isopropyl alcohol was proposed to be classified as Category IIIE,
and benzalkonium chloride was proposed to be classified as Category
IIISE for use in an antiseptic hand wash or healthcare personnel hand
wash. However, in the 2016 Consumer Antiseptic Rub proposed rule, we
proposed to classify all three ingredients as Category IIISE for use in
a consumer antiseptic rub because additional effectiveness and safety
data are needed to classify each ingredient as GRAS/GRAE for this use.
    FDA has deferred further rulemaking on these three active
ingredients for use in OTC consumer antiseptic rubs to allow for the
development and submission to the record of new safety and
effectiveness data for these three ingredients. Therefore, we do not
make a GRAS/GRAE determination for these three active ingredients in
this document. The monograph or nonmonograph status of these three
ingredients will be addressed, either after completion and analysis of
studies to address the safety and effectiveness data gaps of these
ingredients or at another time, if these studies are not completed. As
discussed below, this document describes the studies necessary as a
scientific matter for the Agency to determine whether an active
ingredient is GRAS/GRAE for use in consumer antiseptic rubs.
2. Ineligible Active Ingredients
    The following list includes those active ingredients addressed in
the 1994 TFM for use in antiseptic hand washes or healthcare personnel
hand washes and identified in the 2016 Consumer Antiseptic Rub proposed
rule as having inadequate evidence of eligibility for evaluation under
the OTC Drug Review for use in an OTC consumer antiseptic rub:

 Benzethonium chloride
 Chloroxylenol
 Chlorhexidine gluconate \2\
---------------------------------------------------------------------------

    \2\ Chlorhexidine gluconate 4 percent aqueous solution was also
found to be ineligible for inclusion in the monograph for any
healthcare antiseptic use and was not included in the 1994 TFM (59
FR 31402 at 31413). We have not received any new information since
the 1994 TFM demonstrating that this active ingredient is eligible
for the topical antimicrobial monograph.
---------------------------------------------------------------------------

 Cloflucarban
 Fluorosalan
 Hexachlorophene
 Hexylresorcinol

 Iodine complex (ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate)
 Iodine complex (phosphate ester of alkylaryloxy polyethylene
glycol)
 Methylbenzethonium chloride
 Nonylphenoxypoly (ethyleneoxy) ethanoliodine
 Phenol (equal to or less than 1.5 percent or greater than 1.5
percent)
 Poloxamer iodine complex
 Povidone-iodine 5 to 10 percent
 Secondary amyltricresols
 Sodium oxychlorosene
 Tribromsalan
 Triclocarban
 Triclosan
 Triple dye
 Undecoylium chloride iodine complex

    In addition, as previously described in the 2016 Consumer
Antiseptic Rub proposed rule, FDA received several submissions in
response to the 1994 TFM requesting that the compounds identified below
be included in the monograph:

 Polyhexamethylene biguanide
 Benzalkonium cetyl phosphate
 Cetylpyridinium chloride
 Salicylic acid
 Sodium hypochlorite
 Tea tree oil
 Combination of potassium vegetable oil solution, phosphate
sequestering agent, and triethanolamine

    These compounds were not addressed prior to the 1994 TFM in FDA
documents related to the topical antimicrobial monograph and were not
evaluated for antiseptic hand wash use by the Advisory Review Panel on
OTC Topical Antimicrobial I Drug Products (Antimicrobial I Panel),
which was the advisory review panel responsible for evaluating data on
the active ingredients in this drug class.
    In addition, in the 1994 TFM (59 FR 31402 at 31435) FDA proposed
that the active ingredients fluorosalan, hexachlorophene, phenol
(greater than 1.5 percent), and tribromsalan be classified as not GRAS/
GRAE for the uses referred to in the 1994 TFM as antiseptic hand wash
and healthcare personnel hand wash. In the 2016 Consumer Antiseptic Rub
proposed rule, FDA explained that it would not discuss the efficacy and
safety information regarding these ingredients that had been submitted
to the rulemaking because none of the four active ingredients had
adequate evidence of eligibility for evaluation under the OTC Drug
Review for use in an OTC consumer antiseptic rub (81 FR 42912 at
42918).
    FDA also explained in the 2016 Consumer Antiseptic Rub proposed
rule that if appropriate documentation was submitted for a proposed
ineligible active ingredient, we could determine that the active
ingredient was eligible for evaluation under the OTC Drug Review for
use in an OTC consumer antiseptic rub. We have not received any
information or documentation for the 28 active ingredients identified
as ineligible in the 2016 Consumer Antiseptic Rub proposed rule since
the proposed rule's publication demonstrating that these active
ingredients are eligible for evaluation under the OTC Drug Review for
inclusion in the OTC consumer antiseptic rub monograph. Accordingly,
OTC consumer antiseptic rub drug products containing any of these
ineligible active ingredients are new drugs under section 201(p) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 321(p)) for
which approved applications under section 505 of the FD&C Act (21
U.S.C. 355) and part 314 (21 CFR part 314) of the regulations are
required for marketing and which may be misbranded under section 502 of
the FD&C Act (21 U.S.C. 352).

D. Updated Statistical Analysis for Efficacy

    In the 1994 TFM, FDA recommended that the general effectiveness of
antiseptics be assessed in several ways, including by conducting
clinical simulation studies with the surrogate endpoint of the number
of bacteria removed from the skin. In the 2015 Health Care Antiseptic
proposed rule and the 2016 Consumer Antiseptic Rub proposed rule, FDA
made revisions to the effectiveness criteria proposed in the 1994 TFM,
while continuing to recommend that bacterial log reduction studies be
used to demonstrate that an active ingredient is GRAE for use in a
consumer antiseptic rub product. FDA recommended that these bacterial
log reduction studies: (1) Include both a negative control (test
product vehicle or saline solution) and an active control (an FDA-
approved product); (2) have an adequate sample size to show that the
test product is superior to its negative control; (3) incorporate the
use of an appropriate neutralizer and a demonstration of neutralizer
validation; and (4) include an analysis of the proportion of subjects
who meet the recommended log reduction criteria based on a two-sided
statistical test for superiority to negative control and a 95 percent
confidence interval approach (81 FR 42912 at 42921 to 42922). FDA also
recommended that the success rate or responder rate of the test product
be significantly higher than 70 percent. This meant that the lower
bound of the 95 percent confidence interval for the proportion of
subjects who met the log reduction criteria was expected to be at least
70 percent.
    Consistent with the 1994 TFM, the 2015 Health Care Antiseptic
proposed rule, the 2016 Consumer Antiseptic Rub proposed rule, and the
2017 Health Care Antiseptic FR, we find that bacterial log reduction
studies should continue to be used to demonstrate that an active
ingredient is effective for use in a consumer antiseptic rub product.
Also, consistent with the 2015 Health Care Antiseptic proposed rule,
the 2016 Consumer Antiseptic Rub proposed rule, and the 2017 Health
Care Antiseptic final rule, subjects should be randomized to a three-
arm study: Test, active control, and negative control (the test
product's vehicle or saline solution). However, as outlined in the
consumer antiseptic rub deferral letters (Ref. 7) and based on comments
submitted on the 2015 Health Care Antiseptic proposed rule and the
Agency's further evaluation of additional data, we have updated the
statistical analysis related to the log reduction criteria for
classifying consumer antiseptic rub active ingredients as GRAE. This
updated statistical analysis is consistent with the statistical
analysis set forth in the 2017 Health Care Antiseptic final rule.
    Rather than using only a change in bacterial count from baseline,
the updated analysis uses the average treatment effect (ATE), an
estimated difference of the effect of two treatments correcting for
baseline count. The ATE is estimated from a linear regression of post-
treatment bacterial count (log10 scale) on the additive
effect of a treatment indicator and the baseline or pre-treatment
measurement (log10 scale). The updated analysis is designed
to assess whether the ATEs across subjects meet specific conditions of
superiority and non-inferiority, rather than whether the percentage of
subjects who meet a specific threshold significantly exceeds 70
percent. Under the updated analysis, products must show non-inferiority
of test product to active control by a margin of 0.5 (log10
scale) and superiority of test product to negative control by a margin
of 1.5 (log10 scale). In the conditions below, the ATE of
the test product compared to the negative control is defined as the
contrast of treatment effect of negative control minus the treatment
effect of the test drug in the linear regression. Likewise, the ATE of
the active control compared to the test product is defined as the
contrast of treatment effect of test product minus the treatment effect
of

the active control in the linear regression.
    Superiority to negative control by a specific margin is needed
because our evaluation suggests that application of a negative control,
whether the test product's vehicle or saline, may exhibit some minimal
antimicrobial properties. Thus, using superiority to negative control
by those margins will help ensure that we can appropriately assess the
effectiveness of the antimicrobial products. The margins we identify in
this section were derived from review and analysis of existing data and
may be revised as data gaps on deferred antimicrobial products are
filled. Because of existing data gaps, we also require the deferred
ingredient to show non-inferiority to active controls by a 0.5 margin
(log10 scale).
    Accordingly, based on the updated analysis, the bacterial log
reduction studies used to assess whether an active ingredient is
effective for use in consumer antiseptic rubs should include the
following:
     The test product should be non-inferior to an FDA-approved
antiseptic rub as active control with a 0.5 margin (log10
scale). That is, we expect the upper bound of the 95 percent confidence
interval of the ATE of the active control compared to the test product
to be less than 0.5 (log10 scale). An active control is not
intended to validate the study conduct or to show superiority of the
test drug product but to show that the test drug product is not
inferior to the control. Non-inferiority to active control should be
met on each hand within 5 minutes after a single rub for the consumer
antiseptic rub indication.
     The test product should be superior to the negative
control by a margin of 1.5 (log10 scale). That is, we expect
the lower bound of the 95 percent confidence interval of the ATE of the
test product compared to the negative control to be greater than 1.5
(log10 scale). In cases where the vehicle cannot be used as
a negative control, saline solution can be used. Based on our
evaluation of the existing data, for the consumer antiseptic rub
indication a superiority margin of 1.5 (log10 scale) should
be met on each hand within 5 minutes after a single rub.
     Include a minimum sample size of 100 subjects per
treatment arm. The study can have a larger sample size in each
treatment arm to meet criteria for non-inferiority and superiority
after assessment of variability.
     Conduct two adequate and well-controlled clinical
simulation pivotal studies for the consumer antiseptic rub indication
at two separate independent laboratory facilities by independent
principal investigators.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    In response to the 2016 Consumer Antiseptic Rub proposed rule, we
received approximately 47 comments from an animal rights organization,
healthcare professionals, a manufacturer, trade associations, and
individuals. We also received additional data and information for
certain deferred consumer antiseptic rub active ingredients.
    We describe and respond to the comments in sections V.B. through
V.E. We have numbered each comment to help distinguish among the
different comments. We have grouped similar comments together under the
same number, and in some cases, we have separated different issues
discussed in the same comment and designated them as distinct comments
for purposes of our responses. The number assigned to each comment or
comment topic is purely for organizational purposes and does not
signify the comment's value, importance, or the order in which comments
were received.

B. General Comments on the Proposed Rule and FDA Response

1. Definition of Consumer Antiseptic Rubs
    (Comment 1) We received comments asking FDA to revise the
definition of consumer antiseptic rubs. In the 2016 Consumer Antiseptic
Rub proposed rule, we stated that consumer antiseptic rubs are products
that are intended to be used when soap and water are not available and
are left on and not rinsed off with water (81 FR 42912 at 42913). These
comments asked FDA to define consumer antiseptic rubs as products
``that are intended for use when hands are not visibly soiled, or when
soap and water are not practical or available and are not intended to
be rinsed off with water.''
    (Response 1) We decline to revise the definition of consumer
antiseptic rubs to add information about using or not using consumer
antiseptic rubs when hands are visibly soiled. In general, information
about when and how to use a drug product is contained in the product's
label. In this case, the label is the appropriate place for information
about using or not using consumer antiseptic rub products when hands
are visibly soiled. Integrating information about such use into the
definition of consumer antiseptic rubs could be problematic because
whether a consumer antiseptic rub product can be used when hands are
visibly soiled could depend on the particular product's final
formulation.
    We also decline to incorporate the concept of practicality into the
consumer antiseptic rub's definition. It is unclear what it means to
say that soap and water are not ``practical,'' or how not ``practical''
differs from not ``available.'' We do not think that adding the word
``practical'' helps to define the category of consumer antiseptic rubs
or to differentiate consumer antiseptic rubs from other products. For
these reasons, we will continue to define consumer antiseptic rubs as
products that are intended to be used when soap and water are not
available and are left on and not rinsed off with water (81 FR 42912 at
42913).
2. GRAS/GRAE Classification of Alcohol
    (Comment 2) Several comments requested that FDA reconsider its
proposal in the 2016 Consumer Antiseptic Rub proposed rule to classify
alcohol as a Category III (available data are insufficient to classify
as safe and effective, and further testing is necessary) active
ingredient. In the 1994 TFM, alcohol was proposed to be classified as a
Category I (generally recognized as safe and effective and not
misbranded) topical antiseptic ingredient for certain indications. Two
comments argued that FDA has provided no data to indicate that there is
a safety or efficacy concern or issue with alcohol. These comments
noted that during the September 3, 2014, NDAC meeting, several NDAC
members argued in favor of continuing to categorize alcohol as Category
I while further testing is conducted to fill the data gaps about its
safety.
    (Response 2) As we explained in the 2017 Health Care Antiseptic
final rule, we classify ingredients as Category I, Category II (not
generally recognized as safe and effective or misbranded), and Category
III until the final monograph stage, at which point we use the term
``monograph conditions'' in place of Category I, and the term
``nonmonograph conditions'' in place of Categories II and III (82 FR
60474 at 60482). In the 1994 TFM, alcohol was proposed to be classified
as Category I for use in ``antiseptic hand wash'' products, which
included consumer antiseptic rubs (59 FR 31402 at 31433). In the 2016
Consumer Antiseptic Rub proposed rule, we changed the proposed
classification of alcohol for use in consumer antiseptic rubs from
Category I to III, because we found that there were not enough data on
alcohol to meet our proposed safety data requirements

(81 FR 42912 at 42918 to 42919, 42928). We explained that there had
been many important scientific developments since 1994 that affected
our evaluation of the safety of the active ingredients in consumer
antiseptic rub products and that this, in turn, had caused us to
reassess the data necessary to support a GRAS determination (81 FR
42912 at 42923). These developments include new information regarding
systemic exposure to antiseptic active ingredients, the need to
evaluate the potential for widespread antiseptic use to promote the
development of antibiotic-resistant bacteria, and improved study
designs that are more capable of detecting a potential safety risk. In
the case of alcohol, we explained that the available data
characterizing the level of dermal absorption and expected systemic
exposure in adults as a result of topical use of alcohol-containing
antiseptics do not cover maximal use of these products (81 FR 42912 at
42928). Therefore, we determined that the data regarding the safety of
alcohol were insufficient to make a GRAS determination without human
pharmacokinetic (PK) studies under maximal usage trial (MUsT)
conditions when applied topically, including documentation of
validation of the methods used to measure alcohol and its metabolites.
3. Requests for Deferrals of Final Rulemaking
    (Comment 3) We received comments requesting that FDA defer
rulemaking on the three active ingredients eligible for use in OTC
consumer antiseptic rub products to allow for the development and
submission to the record of new safety and effectiveness data for these
active ingredients. One comment asserted that the studies FDA proposed
could take several years to design, execute, analyze, and report, and
requested that FDA defer rulemaking for alcohol and benzalkonium
chloride. Another comment contended that the differences in the testing
requirements between the 1994 TFM and the 2016 Consumer Antiseptic Rub
proposed rule warrant an extension of time to determine essential
studies that may be needed for isopropyl alcohol, protocols for those
studies, review of any data generated, and submission of the data to
FDA.
    (Response 3) As explained earlier, in response to several requests
submitted to the 2016 Consumer Antiseptic Rub proposed rule, FDA has
deferred further rulemaking on the three active ingredients eligible
for use in OTC consumer antiseptic rub products to allow for the
development and submission to the record of new safety and
effectiveness data for these ingredients. The deferred active
ingredients are benzalkonium chloride, alcohol (also referred to as
ethanol or ethyl alcohol), and isopropyl alcohol. For each active
ingredient, FDA has deferred rulemaking for 1 year, with the
possibility of renewal, which allows the Agency to monitor the
continued progress of the studies being conducted (Ref. 7).
4. Labeling
    (Comment 4) One comment stated that the labeling of consumer
antiseptic rub products should contain the established name of the drug
and identify the product using ``Antiseptic Rub,'' ``Antiseptic Hand
Rub,'' ``Antimicrobial rub,'' ``Antimicrobial hand rub,'' ``Hand
Sanitizer,'' ``Antiseptic Hand Sanitizer,'' or ``Antimicrobial Hand
Sanitizer.'' The comment contended that ``Hand Sanitizer'' is the term
that is the most recognized and understood by consumers and that a
change in terminology could cause confusion. The comment also
recommended that FDA clarify that the Drug Facts label for consumer
antiseptic rubs can use the header ``Use/s'' in place of
``Indication,'' since ``Use'' is more easily understood by consumers,
and also recommended certain terminology to describe the products' use.
In addition, the comment proposed that the ``Directions'' section of
the Drug Facts label for consumer antiseptic rubs reflect the
parameters used when product efficacy was demonstrated. Other comments
proposed that the Directions section include clear and specific
instructions for proper use, such as the number of pumps required to
adequately coat the hand, as well as information on products' shelf
lives.
    (Response 4) As we explained in the 2016 Consumer Antiseptic Rub
proposed rule, the labeling for consumer antiseptic rub products
containing a particular active ingredient will be addressed as part of
the final rule if FDA determines that the active ingredient is GRAS/
GRAE (81 FR 42912 at 42913). Because all three of the active
ingredients that are eligible for evaluation for use in consumer
antiseptic rubs have been granted deferrals, and FDA has not yet made a
GRAS/GRAE determination on these ingredients, we do not address their
labeling in this document. If any of the three active ingredients are
subsequently found to be GRAS/GRAE, we will address the labeling for
products containing that active ingredient in the applicable final
monograph.
5. Implementation and Compliance
    (Comment 5) We received comments stating that one benefit of the
consumer antiseptic rub rulemaking is that consumer antiseptic rub
products containing potentially harmful active ingredients will be
removed from the market. One comment asked what steps FDA will take to
remove ``substandard'' products from the market.
    (Response 5) In section VII, we explain that we recognize that
manufacturers will need time to comply with this document. Thus, as
proposed in the 2016 Consumer Antiseptic Rub proposed rule (81 FR 42912
at 42930 to 42931), this document will be effective 1 year after the
date of the document's publication in the Federal Register. On or after
that date, any OTC consumer antiseptic rub drug product containing an
active ingredient that we have found in this document to be ineligible
for consideration under the OTC Drug Review for the OTC consumer
antiseptic rub monograph cannot be introduced or delivered for
introduction into interstate commerce unless it is the subject of an
approved NDA or ANDA. FDA strives to minimize risk to consumers by
monitoring the market and, where appropriate, undertaking efforts to
remove violative OTC drug products from the market.
6. Public Education
    (Comment 6) A number of comments included questions or concerns
about the ways in which FDA communicates with consumers about the
antiseptic rulemakings. One comment asked how the general public is
notified of the Agency's findings. Another comment argued that
educating the public on antiseptic products is necessary because the
products' labeling lacks specificity and because consumers may not take
the time to read the labeling. Another comment asked FDA to be cautious
in its communications with consumers about the Agency's work on the
antiseptic monographs. This comment pointed to a September 12, 2016,
posting on FDA's website entitled ``Antibacterial Soap? You Can Skip
It--Use Plain Soap and Water.'' The comment argued that the headline
misleadingly implies that antibacterial soaps in any setting (and also,
by implication, potentially any topical antimicrobial product) do not
work. This comment also criticized FDA's claim that antibacterial soaps
``may do more harm than good over the long term.'' The comment asked
that FDA be clear in its communications that alcohol

(when used as an active ingredient in topical antiseptic products) has
no known safety signals and there is no reason to believe that alcohol-
based hand sanitizers are associated with creating ``supergerms'' or
antibacterial resistant organisms.
    (Response 6) FDA communicates about its various activities,
including the findings it has made as part of the antiseptic
rulemaking, in several ways. Each of the various antiseptic rulemakings
has an official docket, which is publicly available and can be accessed
at https://www.regulations.gov. These dockets contain the proposed and
final rules in which FDA sets forth its findings, along with various
supporting documents. FDA also communicates with the public through our
website. The entire rulemaking history for OTC antiseptic products can
be found at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. In addition, FDA communicates with Congress, consumers,
industry, and other stakeholders, such as patient advocacy groups and
professional associations, through press releases and our accounts on
social media sites, including Facebook, Twitter, and LinkedIn. We
appreciate and will take under consideration the commenters'
suggestions regarding our communications with consumers about the
antiseptic rulemakings.
7. Overlapping Data Requirements and Collections
    (Comment 7) We received comments asking that data that are
collected to fill in a data gap for one antiseptic indication or in
response to one proposed or final rule also be applied to fill in data
gaps for other antiseptic indications or rules. The comments stated
that studies conducted and data submitted to support a finding that an
active ingredient is GRAS/GRAE for a healthcare antiseptic indication
or for use as a consumer antiseptic wash should also provide sufficient
support for a finding that the ingredient is GRAS/GRAE for use as a
consumer antiseptic rub. One comment argued that safety and efficacy
data submitted for the healthcare personnel hand rub use will be
particularly relevant to the consumer antiseptic hand rub use. The
comments specifically anticipated that MUsT studies performed to
support healthcare indications would also support consumer indications,
because maximal usage in a healthcare setting would exceed maximal
usage in the various consumer settings. Because of this, the comments
asked FDA to consolidate MUsT requirements and testing between the
different indications and the different monographs to minimize the
number of trials needed.
    (Response 7) Whenever it is scientifically appropriate to do so,
publicly available efficacy and safety data developed to support one
use of an antiseptic active ingredient may be cross referenced to
support other uses. Generation of duplicative data is not necessary. We
agree that the PK data generated from a MUsT study that is sufficient
to support a healthcare antiseptic indication will also be sufficient
to support a consumer antiseptic indication, because the maximal usage
across consumer settings is lower than the maximal usage in a
healthcare setting.

C. Comments on Effectiveness and FDA Response

1. In Vitro Testing
    (Comment 8) One comment requested that FDA clarify the in vitro
testing requirements that the Agency proposed in the 2016 Consumer
Antiseptic Rub proposed rule for evaluating active ingredients for use
in consumer antiseptic rubs (81 FR 42912 at 42921). The comment asked
whether FDA is requiring minimum bactericidal concentration (MBC),
minimum inhibitory concentration (MIC), and time-kill testing using the
bacteria specified in the 2016 Consumer Antiseptic Rub proposed rule
(81 FR 42912 at 42921). The comment then asked whether time-kill
testing alone would suffice to meet the in vitro testing requirements.
Finally, the comment asked why FDA did not provide an American Type
Culture Collection (ATCC) number for the three strains of gram-negative
bacteria specified in the 2016 Consumer Antiseptic Rub proposed rule--
Haemophilus influenzae, Bacteroides fragilis, and Enterobacter species.
    (Response 8) The in vitro testing requirements for consumer
antiseptic rubs are specified in the 2016 Consumer Antiseptic Rub
proposed rule (81 FR 42912 at 42921). We require MBC or MIC testing of
25 representative clinical isolates and 25 reference (e.g., ATCC)
strains of each of the microorganisms listed in section VII.B.1 of the
2016 Consumer Antiseptic Rub proposed rule (81 FR 42912 at 42921). We
also require time-kill testing of each microorganism and ATCC strain
listed in section VII.B.1 of the 2016 Consumer Antiseptic Rub proposed
rule (81 FR 42912 at 42921). Alternative approaches to filling the
relevant data gaps are unlikely to be sufficient.
    The Agency has not specified ATCC strain numbers for H. influenzae,
B. fragilis, and Enterobacter species in order to provide manufacturers
with options for conducting the necessary studies. Manufacturers may
select any available strain of these bacteria. For MBC or MIC testing,
25 representative clinical isolates and 25 reference (ATCC) strains of
each one of these organisms (H. influenzae, B. fragilis, and
Enterobacter species) are necessary. For time-kill testing, any one
ATCC strain for these three organisms is sufficient.
2. In Vivo Testing
    (Comment 9) We received comments on the in vivo efficacy testing
requirements that the Agency proposed in the 2016 Consumer Antiseptic
Rub proposed rule for evaluating active ingredients for use in consumer
antiseptic rubs (81 FR 42912 at 42921). One comment asked that we
confirm that the following test conditions are suitable:
     Two pivotal studies would be conducted.
     A single use wash would be applied.
     A physiological saline solution would be used as the
control.
     Avagard, the only healthcare personnel hand rub approved
under an NDA would be used as the active control, if pilot studies
confirm its appropriateness.
    (Response 9) Based on the updated statistical analysis for efficacy
that we outline in section IV.D., we confirm that two adequate and
well-controlled clinical simulation pivotal studies should be conducted
for the consumer antiseptic rub indication at two separate independent
laboratory facilities by independent principal investigators. These
studies should include a minimum sample size of 100 subjects per
treatment arm for each of the deferred ingredients (alcohol,
benzalkonium chloride, and isopropyl alcohol). This sample size will
ensure that the ATE will be estimated precisely for the deferred
ingredients and can be used for future reference in final product
monographs. To determine the minimum sample size, FDA analyzed several
studies that included a wide range of sample sizes and concluded that a
minimum of 100 subjects is appropriate to support the external validity
of the results. We note that establishing a minimum sample size of 100
subjects per study arm was not solely based on statistical
considerations; multiple factors, including robustness and sensitivity
of

log reduction to experimental conditions, were taken into account. The
study could have a larger sample size to meet the criteria for non-
inferiority and superiority after an assessment of variability.
    We also confirm that it is appropriate to study a single rub
application of the active ingredient being tested for use as a consumer
antiseptic rub. In the 2016 Consumer Antiseptic Rub proposed rule, we
proposed revisions to the log reduction criteria for consumer
antiseptic rubs based on the recommendations of the March 2005 NDAC
meeting and comments to the 1994 TFM, which argued that the
demonstration of a cumulative antiseptic effect for these products is
unnecessary (81 FR 42912 at 42922). We agreed that the critical element
of effectiveness is that a product must be effective after the first
application because that represents the way in which consumer
antiseptic hand rubs are used. Given that we are no longer requiring a
cumulative antiseptic effect, the efficacy criteria were revised to
reflect a single product application.
    Finally, as noted in section IV.D., with regard to the negative
control used in the studies, saline solution is appropriate, but only
if the test vehicle cannot be used. With regard to the active control
used in the studies, an FDA-approved antiseptic rub product should be
selected. We have discussed and will continue to discuss the selection
of an appropriate active control with the manufacturers and trade
organizations that requested the deferrals for alcohol, benzalkonium
chloride, and isopropyl alcohol (see Docket Nos. FDA-2015-N-0101 and
FDA-2016-N-0124 at https://www.regulations.gov).
    (Comment 10) Comments proposed that the Agency recognize specific
ASTM (American Society for Testing and Materials International)
protocols as standardized test methods for demonstrating that an active
ingredient is GRAE for use in consumer antiseptics. These ASTM
protocols include ASTM E2755-15 ``Standard Test Method for Determining
the Bacteria-Eliminating Effectiveness of Healthcare Personnel Hand Rub
Formulations Using Hands of Adults,'' ASTM E1054-08 ``Standard Test
Methods for Evaluation of Inactivators of Antimicrobial Agents'', and
ASTM E2783-11 ``Standard Test Method for Assessment of Antimicrobial
Activity for Water Miscible Compounds Using a Time-Kill Procedure.''
    (Response 10) We have reviewed these test methods and believe they
may be useful to help establish GRAE status for the three deferred
antiseptic active ingredients for use in consumer antiseptic rub
products. We are currently discussing with manufacturers and trade
organizations that requested the deferrals how these test methods may
be used to meet the current effectiveness criteria (see Docket Nos.
FDA-2015-N-0101 and FDA-2016-N-0124 at https://www.regulations.gov).
    (Comment 11) Comments were submitted that addressed the testing
requirements for the final formulations of specific consumer antiseptic
rub products. Comments argued that neither MIC nor MBC testing should
be necessary for final formulations. The comments contended that an in
vitro time-kill study against an appropriate list of relevant
microorganisms would suffice; one comment set forth specific
recommendations for the conduct of such a study.
    With regard to in vivo efficacy testing requirements, comments
argued that full-scale pivotal studies of final formulations should not
be necessary, because less burdensome testing can confirm that a
product's formulation has not inhibited the activity of the active
ingredient. Comments suggested confirmatory in vivo testing comparing a
finally formulated product to an active control after a single use. One
comment argued that an active ingredient that was found to be GRAS/GRAE
should be the active control, not an approved product. The comment
noted that the only approved alcohol-based hand sanitizer has two
active ingredients. Another comment proposed a specific study design
with recommended success criteria.
    Finally, one comment recommended that a dermatological evaluation
be conducted on finally formulated consumer antiseptic rub products to
ensure skin safety.
    (Response 11) In this document, we do not find any active
ingredients GRAS/GRAE for use as a consumer antiseptic rub. As a
result, this document does not specifically address requirements for
anticipated final formulation testing. The testing requirements for
finally formulated products containing one of the three deferred active
ingredients will be addressed after one or more of the active
ingredients are found to be GRAS/GRAE for use in consumer antiseptic
rub products.

D. Comments on Safety and FDA Response

1. Need for Additional Safety Data
    (Comment 12) One comment objected to the fact that FDA based its
decision to require additional safety data on the fact that systemic
exposure is higher than previously thought, and new information is
available about the potential risks from systemic absorption and long-
term exposure (80 FR 42912 at 42923). The comment argued that before
FDA could require additional safety data, it would need to present
``definitive evidence'' that systemic exposure is higher than
previously thought. The comment also argued that the evidence should
consist of either in vitro or dose-dependent data, and not risk,
because, the comment explained, the commenter was unaware of FDA's
current thinking regarding risk assessment.
    (Response 12) We do not agree that FDA can only require additional
safety data if there is ``definitive evidence'' in the form of in vitro
or dose-dependent data that systemic exposure is higher than we
believed it to be when the 1994 TFM was published. In the 2016 Consumer
Antiseptic Rub proposed rule, we explained that, since the 1994 TFM was
published, new data have become available indicating that systemic
exposure to topical antiseptic active ingredients may be greater than
previously thought. Because of advances in technology, our ability to
detect antiseptic active ingredients in body fluids such as serum and
urine is greater than it was in 1994. For example, studies have shown
detectable blood alcohol levels after use of alcohol-containing hand
rubs (Refs. 8 to 10). Given the frequent repeated use of consumer
antiseptic rubs, systemic exposure may occur. Although some systemic
exposure data exist for all three deferred consumer antiseptic rub
active ingredients, data on systemic absorption after maximal use are
lacking. We believe that the degree of systemic exposure should be
determined, and its consequences assessed, to support our risk-benefit
analysis for consumer antiseptic rub use.
    (Comment 13) Some comments argued that FDA should do a more robust
analysis of existing safety data about human exposure and risk and that
this analysis should precede any proposal requiring additional testing.
Comments also argued that, in declining to find ingredients GRAS based
on existing information, FDA is inappropriately discounting the
significant human marketing experience and global acceptance of
consumer antiseptic hand rub products and the low incidence of adverse
events. The comments assert that the low incidence of adverse events is
evidenced by the fact that FDA's Safety Information and

Adverse Event Reporting Program, MedWatch, contains no safety-related
complaints related to topical antiseptic products, and by the fact that
FDA has not issued any safety alerts regarding such products. A comment
also stated that the Nurses' Health Studies, which are a series of
long-term studies of health outcomes in several large cohorts of
nurses, provide evidence of the safety of topical antiseptics. The
comment asserted that these studies did not show any evidence that the
use of topical antiseptic products leads to adverse health outcomes in
nurses.
    (Response 13) FDA summarized the existing data and information on
the three deferred active ingredients alcohol, benzalkonium chloride,
and isopropyl alcohol in the 2016 Consumer Antiseptic Rub proposed rule
(81 FR 42912 at 42927 to 42930). As explained in the 2016 Consumer
Antiseptic Rub proposed rule, the existing data and information support
the conclusion that there is the potential for systemic exposure to
antiseptic active ingredients through repeated dermal applications. At
the same time, we lack the PK data that would tell us precisely the
degree of systemic exposure under maximal use conditions. In addition,
in vivo animal safety and toxicokinetic data are lacking for some
ingredients. Both human and animal data are needed to determine the
safety margin for OTC human use. If there is publicly available data or
information regarding the three deferred active ingredients that FDA
has not found or has overlooked, that information can be submitted to
the docket and considered by the Agency.
    (Comment 14) One comment argued that FDA should consider the level
of human exposure to each of the antimicrobial active ingredients and
assess the potential for harm from those exposures prior to determining
the need for additional safety data. The comment states that in
assessing exposure to active ingredients in consumer antiseptic rub
products, FDA should allow alternative methods to MUsT studies,
including physiologically based pharmacokinetic (PBPK) models and
potentially other animal or human studies. The comment also states that
FDA should provide additional guidance on how a MUsT study may be
conducted in a reasonable manner.
    (Response 14) In the 2017 Health Care Antiseptic final rule, we
explained that the MUsT paradigm has been used in the evaluation of
topical dermatological agents approved in the United States since the
early 1990s (82 FR 60474 at 60492 to 60493). It represents over 20
years of interactions with multinational drug companies, during which
time the study design has been refined into its current state.
Moreover, the MUsT is a published methodology that has been presented
at both national and international meetings. We also explained that we
understand and recognize the potential of PK and PBPK modeling. FDA has
considered these options and others and has concluded that currently,
they are not validated adequately to substitute for the MUsT described
in the 2016 Consumer Antiseptic Rub proposed rule (81 FR 42912 at 42923
to 42924) and the 2015 Health Care Antiseptic proposed rule (80 FR
25166 at 25182). FDA has been reviewing the MUsT protocol designs
submitted by the manufacturers and trade organizations that requested
deferrals of the three consumer antiseptic rub active ingredients and
is currently discussing protocol design issues with these manufacturers
and trade organizations.
    With regard to the recommendation that FDA provide guidance on MUsT
studies, in May 2018 the Agency issued a draft guidance for industry
entitled ``Maximal Usage Trials for Topical Active Ingredients Being
Considered for Inclusion in an Over-The-Counter Monograph: Study
Elements and Considerations'' (Ref. 11). The guidance, when finalized,
will outline FDA's recommendations for designing and conducting a MUsT,
which, based on input from the NDAC, FDA has determined is generally
important to support a GRAS/GRAE determination for a topical active
ingredient. The guidance, when finalized, will address critical study
elements, data analysis, and considerations for special topic areas
(e.g., pediatrics, geriatrics). The guidance, when finalized, will also
encourage study sponsors to seek feedback from FDA on their overall
approach and the design of a particular study.
    (Comment 15) One comment argued that FDA should not require
additional carcinogenicity studies for benzalkonium chloride. This
comment stated that a good quality systemic carcinogenicity data set
exists for benzalkonium chloride, along with data from in vitro genetic
toxicology studies. The comment contended that, given that no tumors
developed in an oral study of the product, and provided that good
quality in vitro genetic toxicity data are available, a dermal study
should not be necessary. The comment also contended that it is highly
unlikely that the dermal route of administration would result in a
higher systemic exposure than the oral route of administration.
    (Response 15) As we stated in the 2016 Consumer Antiseptic Rub
proposed rule, no dermal carcinogenicity studies of benzalkonium
chloride have been submitted to FDA (81 FR 42912 at 42929). Although,
as the comment states, we have data generated by two oral
carcinogenicity studies, the potential for topically applied
benzalkonium chloride to cause skin cancer remains unstudied. There are
no validated methods currently known to the Agency for predicting
dermal carcinogenicity risk from data generated in studies that
employed a non-dermal route of administration. As we explained in the
2016 Consumer Antiseptic Rub proposed rule, the magnitude of exposure
to the skin from a topical product can be much higher than would be
covered by systemic studies (81 FR 42912 at 42926). In addition,
systemic exposure to the parent compound and metabolites can differ
significantly for a dermally applied product because the skin has
metabolic capability and first-pass metabolism is bypassed via this
route of administration (81 FR 42912 at 42926). Data on the potential
for benzalkonium chloride to induce a neoplastic response in the skin
with repeated dermal application are necessary in order to assess the
safety of benzalkonium chloride for use in consumer antiseptic rub
products.
    (Comment 16) One comment stated that there are data suggesting that
some antiseptic active ingredients have hormonal effects. The comment
asked why products containing active ingredients with hormonal effects
are still on the market.
    (Response 16) As we explained in the 2016 Consumer Antiseptic Rub
proposed rule, with the exception of human pharmacokinetic data under
maximal use conditions, there are adequate safety data to determine
that alcohol is GRAS (81 FR 42912 at 42928). This includes adequate
data on the hormonal effects of alcohol in animals and humans.
Similarly, although there are other gaps in the safety data for
benzalkonium chloride, there are adequate data to make a determination
that benzalkonium chloride does not have hormonal effects (81 FR 42912
at 42928 to 42930). With regard to isopropyl alcohol, the existing data
are not adequate to characterize its potential for hormonal effects (81
FR 42912 at 42930). As we explained in section IV.C.1., FDA has
deferred further rulemaking on alcohol, benzalkonium chloride, and
isopropyl alcohol to allow for the development and submission to the
record of new safety and effectiveness data for these ingredients. This
includes the data necessary to

characterize isopropyl alcohol's potential for hormonal effects.
2. Animal Testing Issues
    (Comment 17) Comments argued that numerous scientific and
regulatory bodies have performed exposure-driven risk assessments of
antiseptic products and have not requested the types of animal and
human study data that FDA is requiring before making a finding that
such products are safe. Comments asserted that under standard
international practice, safety evaluations for antiseptic ingredients
are based on conservative assumptions of exposure and potential
differences between species, rather than correlation of findings from
animal toxicity studies to humans based on kinetic information from
both animals and humans.
    One comment requested that FDA expand its discussion of ways in
which animal use may be minimized and feature this discussion more
prominently in rulemaking. These include that efficacy testing take
precedence over safety testing, that sharing of data be required, that
route-to-route extrapolation be accepted for carcinogenicity studies,
and that data from human-relevant, non-animal methods be accepted. This
comment stated that if FDA does not have a policy regarding the use of
alternatives to animal testing, the Agency should thoroughly evaluate
their applicability in each individual case.
    With regard to benzalkonium chloride in particular, one comment
argued that additional animal testing should not be necessary unless
the following conditions are met:
     Use of conservative approaches to calculate the margin of
exposure is inadequate.
     The margin of exposure justifies the need for more data,
but it is not possible to generate the data by non-animal approaches,
such as using PBPK modeling, or through animal alternative test
methods.
     There is a perceived need for all ingredients to have the
same type of information.
    Another comment pointed to proprietary data cited by the
Environmental Protection Agency and the Cosmetic Ingredient Review to
support their findings that benzalkonium chloride is safe for use in
disinfectants and cosmetics. The Cosmetic Ingredient Review report
summarizes data from a tumorigenicity study in mice and rabbits in
which ulceration and inflammation, but no tumors, were observed. The
comment urged FDA to try to obtain these data to avoid duplicative
testing.
    (Response 17) We understand that animal use in tests for the
efficacy and safety of human and animal products has been and continues
to be a concern. FDA is an active partner in efforts to reduce, refine,
or replace (known as the 3Rs) the use of animals in drug development
(Ref. 12). In general, however, there continues to be a need for data
from studies conducted in living, intact mammalian systems, when there
are currently no viable and validated alternatives in place to address
the myriad questions inherent to the drug safety assessment process
including determining the many interrelated local and systemic
endpoints that are of concern in the overall safety assessment for an
ingredient. The animal testing described in the deferral letters for
each of the three deferred consumer antiseptic rub active ingredients
was proposed in response to and in concurrence with NDAC guidance to
generate the publicly available data needed to fill identified data
gaps. The Agency remains open to considering data generated using non-
animal methods.
    We emphasize that FDA does not require that studies in animals be
conducted before studies in humans. In fact, until human MUsT data have
been generated and evaluated, we will not have the evidence of systemic
bioavailability that would trigger the need for certain studies in
animals. The need for studies could also be triggered by an adequately
conducted toxicology program that reveals a safety signal for the
ingredient or for any known structurally similar compound, and thereby,
indicates the potential for adverse effects at exposure levels lower
than those that result from maximal usage. If data generated from
safety or efficacy testing in humans fail to meet the minimum criteria
for a GRAS/GRAE determination, it may not be necessary to conduct
animal studies including a dermal carcinogenicity study, an oral
carcinogenicity study, embryofetal development studies in rodents and
non-rodents, a fertility and early embryonic development study, and a
pre- and post-natal development study.
    With regard to the proposal to incorporate route-to-route
extrapolation in assessing potential carcinogenicity risk, for drug
products whose primary route of administration is via topical dermal
application, a target tissue of concern is the skin and associated
substructures. As we explained earlier, there are no validated methods
currently known to the Agency for predicting dermal carcinogenicity
risk from data generated in studies that employed a non-dermal route of
administration. Data on the potential for the active ingredient under
study to induce a neoplastic response in the skin with repeated dermal
application are necessary in order to assess the safety of alcohol,
benzalkonium chloride, and isopropyl alcohol for use in consumer
antiseptic rub products. If these data adequately confirm a lack of
carcinogenicity potential in the skin and, further, raise no concerns
of any systemic targets of toxicity, and if an adequately conducted
MUsT demonstrates low systemic bioavailability of the active
ingredient, then an oral carcinogenicity study, a fertility and early
embryonic development study, and a pre- and post-natal development
study are unlikely to be necessary to support a GRAS/GRAE
determination, again unless an adequately conducted toxicology program
reveals safety signals for a particular active ingredient or for any
known structurally similar compound. Total animal usage would thereby
be reduced significantly.
3. Bacterial Resistance Testing
    (Comment 18) Comments relating to the issue of bacterial resistance
were submitted in response to the 2016 Consumer Antiseptic Rub proposed
rule. In general, the comments were split with regard to whether
antiseptics pose a public health risk from bacterial resistance. Some
comments agreed that the pervasive use of consumer antiseptic rubs
poses a risk for the development of bacterial resistance. Other
comments disagreed and criticized the data on which they believe FDA
based its concerns.
    Specifically, comments dismissed the in vitro data cited by FDA in
the proposed rule as not reflecting real-life conditions. The comments
argued that the most useful assessment of the risk of biocide
resistance and cross-resistance to antibiotics are in-situ studies,
studies of clinical and environmental strains, or biomonitoring
studies. Some comments asserted that studies of these types have
reinforced the idea that resistance and cross-resistance associated
with antiseptics is a laboratory phenomenon observed only when tests
are conducted under unrealistic conditions. One comment stated that
there is little credible evidence that antiseptic products play any
role in antibiotic resistance in human disease. The comment stated
that, while some in vitro lab studies have been successful in forcing
expression of resistance to antiseptic active ingredients in some
bacteria, real world data from community studies using actual product
formulations show no correlation

between the use of such products and antibiotic resistance. The comment
stated that further evidence of real-world data showing no
antimicrobial resistance development after the continued use of
consumer products containing antimicrobial active compounds can be
extracted from oral care clinical studies, which provide in vivo data,
under well-controlled conditions, on exposure to antimicrobial-
containing formulations over prolonged periods of time (e.g., 6 months
to 5 years). The comment also cited the conclusions of an International
Conference on Antimicrobial Research held in 2012 on a possible
connection between biocide (antiseptic or disinfectant) resistance and
antibiotic resistance to support the point that there is no correlation
between antiseptic use and antibiotic resistance.
    (Response 18) As explained in the 2016 Consumer Antiseptic Rub
proposed rule, we continue to believe that the development of bacteria
that are resistant to antibiotics is an important public health issue,
and that additional data may tell us whether use of antiseptics in
consumer settings may contribute to the selection of bacteria that are
less susceptible to both antiseptics and antibiotics (81 FR 42912 at
42926). Thus, we have conducted ingredient-specific reviews of the
literature pertaining to antiseptic resistance and antibiotic cross-
resistance, and determined that additional studies to assess the
development of cross-resistance to antibiotics are needed for only one
of the deferred active ingredients, benzalkonium chloride. In the case
of ethyl alcohol and isopropyl alcohol, sufficient data have been
provided to assess the risk of antiseptic resistance and antibiotic
cross-resistance.
    Laboratory studies have identified and characterized bacterial
resistance mechanisms that confer a reduced susceptibility to
antiseptics and, in some cases, antibiotics. Specifically, these data
suggest that resistance development in the laboratory is very common
for some active ingredients, such as benzethonium and benzalkonium
chloride (Refs. 13 to 17), and chloroxylenol, used in topical
antiseptic products (Refs. 18 to 23). In contrast, resistance to other
active ingredients, such as povidone-iodine (Refs. 24 to 26) occurs
infrequently in the laboratory setting. We acknowledge that
observations made in the laboratory setting are not necessarily
replicated in the real-world setting. Therefore, we assessed additional
studies performed in the clinical setting.
    Studies performed using clinical isolates found strong evidence of
antiseptic resistance to benzethonium and benzalkonium chloride (Refs.
27 to 35). Antiseptic resistance genes qacA/B and qacE (Ref. 32) were
identified and, in 83 percent and 73 percent of the isolates tested,
respectively, correlated with reduced susceptibility to benzalkonium
and benzethonium chloride. In contrast, two studies published by
Kawamura-Sato et al. (Refs. 36 and 37) found the MIC of benzalkonium
chloride for 283 clinical isolates to be well within in-use
concentration.
    Other studies examined a possible correlation between antiseptic
and antibiotic resistance (Refs. 23 to 34 and 37 to 46). Comparisons
suggest that alterations in the mean susceptibility of Staphylococcus
aureus to antimicrobial biocides occurred between 1989 and 2000, but
these changes were mirrored in both methicillin resistant and
susceptible S. aureus, suggesting that methicillin resistance had
little to do with these changes (Ref. 46). In S. aureus, Escherichia
coli, and Pseudomonas aeruginosa, several correlations (both positive
and negative) between antibiotics and antimicrobial biocides were found
(Refs. 37, 39, 41, 44, 46, and 47). From the analyses of these clinical
isolates, it is very difficult to support a hypothesis that increased
biocide resistance is a cause of increased antibiotic resistance in
these species.
    Bacteria expressing resistance mechanisms with a decreased
susceptibility to antiseptics and some antibiotics have been isolated
from a variety of natural settings (Refs. 48 and 49). Although the
prevalence of antiseptic tolerant subpopulations in natural microbial
populations is currently low, overuse of antiseptic active ingredients
has the potential to select for resistant microorganisms.
    In sum, adequate data do not exist currently to determine whether
the development of bacterial antiseptic resistance could also select
for antibiotic resistant bacteria or how significant this selective
pressure would be relative to the overuse of antibiotics, an important
driver for antibiotic resistance. Moreover, the possible correlation
between antiseptic and antibiotic resistance is not the only concern.
Reduced antiseptic susceptibility may allow the persistence of
organisms in the presence of low-level residues and contribute to the
survival of antibiotic resistant organisms. Data are not currently
available to assess the magnitude of this risk.
    (Comment 19) The comments also addressed the data needed to assess
the risk of the development of resistance. One comment disagreed with
the proposed testing described in the 2016 Consumer Antiseptic Rub
proposed rule, arguing that there are no standard laboratory methods
for evaluating the development of antimicrobial resistance. With regard
to the recommendation for mechanism studies, they believed that it is
unlikely that this kind of information can be developed for all active
ingredients, particularly given that the mechanism(s) of action may be
concentration dependent and combination and formulation effects may be
highly relevant. The comments also argued that data characterizing the
potential for transferring a resistance determinant to other bacteria
is also an unrealistic requirement for a GRAS determination. Finally, a
comment argued that the requirements for data and information should be
able to be satisfied through an ingredient-specific review of the
literature and without generation of new laboratory data.
    (Response 19) In the 2016 Consumer Antiseptic Rub proposed rule, we
described the data needed to help establish a better understanding of
the interactions between antiseptic active ingredients used in consumer
antiseptic rub products and bacterial resistance mechanisms and the
data needed to provide the information necessary to perform an adequate
risk assessment for these consumer antiseptic rub products. We
suggested a tiered approach as an efficient means of developing data to
address this resistance issue, beginning with laboratory studies in
conjunction with a literature review aimed at evaluating the impact of
exposure to nonlethal amounts of antiseptic active ingredients on
antiseptic and antibiotic bacterial susceptibilities, along with
additional data, if necessary, to help assess the likelihood that
changes in susceptibility observed in the preliminary studies would
occur in the consumer setting (81 FR 42912 at 42926 to 42927). As we
explained in the 2016 Consumer Antiseptic Rub proposed rule, we
recognize that the science of evaluating the potential of compounds to
cause bacterial resistance is evolving and acknowledged the possibility
that alternative data may be identified as an appropriate substitute
for evaluating the development of resistance (81 FR 42912 at 42927).
    For benzalkonium chloride, for which resistance testing is
necessary as described in the applicable deferral letter, we have
advised manufacturers, as an initial step, to conduct an active

ingredient-specific literature review related to antiseptic resistance
and antibiotic cross-resistance to assess the active ingredient's
effect on development of cross-resistance to antiseptics and
antibiotics in the consumer setting, and to submit as much information
and data as can be provided (Ref. 50). If the literature review results
show evidence of antiseptic or antibiotic resistance, additional
studies may be necessary, consistent with the recommendations outlined
in the 2016 Consumer Antiseptic Rub proposed rule, to help assess the
impact of the active ingredient on antiseptic and antibiotic
susceptibilities. If, however, the literature review provides no
evidence that the active ingredient affects antiseptic or antibiotic
susceptibility, then it is likely that no further studies to address
development of resistance will be needed to support a GRAS
determination.
4. The Risk of Ingestion and Poisoning
    (Comment 20) Comments raised concerns about the risks of poisoning
from consumer antiseptic rubs containing alcohol and, in particular,
about the risk of ingestion of these products by young children. A
comment recommended that, if consumer antiseptic rubs are used in
schools, that teachers store them in a safe place and that students
only use them with adult supervision. The comment also recommended
using hand sanitizing wipes or products that do not contain alcohol to
reduce the risk of ingestion and poisoning.
    (Response 20) We agree that hand sanitizers or antiseptic wipes
should be stored out of the reach of children and should be used with
adult supervision. We note that the labeling for all drugs marketed
under an OTC monograph is required to contain the general warning
``Keep out of reach of children'' in bold type (21 CFR 330.1(g)). As we
explained in the 2016 Consumer Antiseptic Rub proposed rule, however,
the labeling for consumer antiseptic rub products containing a
particular active ingredient will be addressed as part of the final
rule if FDA makes a determination that the active ingredient is GRAS/
GRAE (81 FR 42912 at 42913). Because all three of the ingredients that
are eligible for consideration as a consumer antiseptic rub, including
alcohol, have been granted deferrals, and FDA has not yet made a GRAS/
GRAE determination for these active ingredients, we do not address
their labeling in this document. If alcohol and/or isopropyl alcohol
are subsequently found to be GRAS/GRAE, we will address its labeling in
the final monograph for that active ingredient. As the comment
suggests, we may consider at that time whether the labeling for
consumer antiseptic rub products containing alcohol should contain
additional directions or warnings aimed at reducing the risk of
ingestion by young children. We may also consider whether using hand
sanitizing wipes or products that do not contain alcohol could reduce
the risk of ingestion and poisoning and, if so, whether and how that
information should be incorporated into labeling.

E. Comments on the Preliminary Regulatory Impact Analysis and FDA
Response

    (Comment 21) One comment raised issues concerning the preliminary
regulatory impact analysis (RIA) and the Agency's assessment of the net
benefit of the rulemaking. The comment stated that FDA's RIA did not
account for all the costs and overestimated the benefits associated
with the proposed regulation. The comment noted that if the active
ingredients in consumer antiseptic rub products are safe, there is no
benefit to avoiding exposure to them. In addition, there are costs
associated with the loss of availability of hand rub antiseptics in
consumer settings.
    (Response 21) Our response is provided in the full discussion of
economic impacts, available in the docket for this document (Docket No.
FDA-2016-N-0124, (Ref. 51), https://www.regulations.gov) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

VI. Effective Date

    In the 2016 Consumer Antiseptic Rub proposed rule, we recognized,
based on the scope of products subject to this final rule, that
manufacturers would need time to comply with this final rule. Thus, as
proposed in the 2016 Consumer Antiseptic Rub proposed rule (81 FR 42912
at 42930 to 42931), this document will be effective 1 year after the
date of the document's publication in the Federal Register. On or after
that date, any OTC consumer antiseptic rub drug products containing an
ingredient that we have found in this document to be ineligible for
consideration under the OTC Drug Review for the OTC consumer antiseptic
rub monograph cannot be introduced or delivered for introduction into
interstate commerce unless it is the subject of an approved NDA or
ANDA.

VII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the document under Executive Order
12866, Executive Order 13563, Executive Order 13771, the Regulatory
Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform
Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct us
to assess all costs and benefits of available regulatory alternatives
and, when regulation is necessary, to select regulatory approaches that
maximize net benefits (including potential economic, environmental,
public health and safety, and other advantages; distributive impacts;
and equity). Executive Order 13771 requires that the costs associated
with significant new regulations ``shall, to the extent permitted by
law, be offset by the elimination of existing costs associated with at
least two prior regulations.'' This final rule is a significant
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Although the additional costs this document imposes on small
entities are small, the consumer antiseptic rub product industry is
mainly composed of establishments with 500 or fewer employees.
Therefore, we find that the document will have a significant economic
impact on a substantial number of small entities. We have analyzed
various regulatory options to examine the impact on small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $154
million, using the most current (2018) Implicit Price Deflator for the
Gross Domestic Product. This document would not result in an
expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    As discussed in the preamble, this document applies to active
ingredients used in OTC consumer antiseptic rub products, including
hand ``sanitizers'' and consumer antiseptic wipes. Here, we refer to
consumer antiseptic rubs or consumer rubs as those products that

are intended to be used when soap and water are not available and are
not intended to be rinsed off with water. An OTC drug is covered by the
OTC Drug Review if its conditions of use existed in the OTC drug
marketplace on or before May 11, 1972 (37 FR 9464). The only active
ingredients eligible for evaluation under the OTC Drug Review for use
in OTC consumer antiseptic rub products are ethyl alcohol (referred to
subsequently as alcohol), isopropyl alcohol, and benzalkonium chloride.
In response to requests submitted to the 2016 Consumer Antiseptic Rub
PR, FDA has deferred regulatory action on these active ingredients.
Accordingly, FDA does not make a GRAS/GRAE determination regarding
these three active ingredients in this document. The monograph or non-
monograph status of these three active ingredients will be addressed,
either after completion and analysis of studies to address the safety
and effectiveness data gaps of these active ingredients or at a later
date, if these studies are not completed.
    This document establishes that all other consumer antiseptic rub
active ingredients are not eligible for consideration under the OTC
Drug Review for use in consumer antiseptic rub products. Drug products
containing the 28 ineligible active ingredients identified in the 2016
Consumer Antiseptic Rub PR will require approval under an NDA or ANDA
prior to marketing. However, we expect that manufacturers of consumer
antiseptic rub products with ineligible active ingredients will either
reformulate and relabel their products to include the three deferred
active ingredients which are eligible for consideration under the OTC
Drug Review, discontinue production of their consumer antiseptic rub
products, or reformulate their products as antiseptic-free topical
cleansers or wipes. In table 4, we provide a summary of the estimated
costs of the document that involve product reformulation and relabeling
of consumer rub products that contain active ingredients that are
ineligible for consideration under the OTC Drug Review for use in
consumer rubs. Manufacturers of consumer antiseptic rub products that
contain the deferred active ingredients may also incur additional costs
associated with the necessary safety and effectiveness testing required
to demonstrate that the deferred active ingredient is GRAS/GRAE.
However, these testing costs are not included in the regulatory impact
analysis for this document because this document does not require any
testing. Although the testing costs are not attributable to this
document, we estimate and present these costs separately in the RIA
analysis.
    We estimate that the present value of the one-time costs associated
with compliance range from $1.07 million to $2.50 million with a
primary estimate of $1.87 million. Annualizing upfront costs over a 10-
year period at a discount rate of 3 percent, the costs of this document
are estimated to be between $0.13 million and $0.29 million per year;
the corresponding estimated cost at a discount rate of 7 percent is
between $0.15 million and $0.36 million per year.
    A potential benefit of this document is that the removal of
potentially harmful antiseptic active ingredients in consumer
antiseptic rub products may prevent health consequences associated with
exposure to such active ingredients. FDA lacks the necessary
information to estimate the impact of exposure to antiseptic active
ingredients in consumer antiseptic rub products on human health
outcomes. We are, however, able to estimate the reduction in the
aggregate exposure to antiseptic active ingredients found in currently
marketed consumer antiseptic rub products. The document will lead to an
estimated reduction in aggregate exposure to benzethonium chloride that
ranges from 110 pounds to 254 pounds per year. This document may also
result in reduced exposure to other ineligible active ingredients.
However, FDA can only estimate the reduced exposure to benzethonium
chloride at this time. Furthermore, we are unable to translate the
aggregate exposure to benzethonium chloride into monetized benefits at
this time because we lack information on the change in the short- and
long-term health risks associated with a 1-pound increase in exposure
to each antiseptic active ingredient in consumer antiseptic rub
products.

                                       Table 4--Summary of Benefits, Costs, and Distributional Effects of Document
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                                                                ------------------------------------
                   Category                       Primary       Low        High                  Discount     Period             Notes  (years)
                                                 estimate    estimate    estimate      Year        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..................  ..........  ..........  ..........  ..........  ..........  ..........  ................................
                                               ------------------------------------------------------------------------

    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 table 5 we estimate present
and annualized values of costs and cost savings over an infinite time
horizon. Based on these costs this document would be considered a
regulatory action under Executive Order 13771.

                                  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 Analysis

    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because many small entities produce consumer
antiseptic rub products, we find that the document will have a
significant economic impact on a substantial number of small entities.
The Final Regulatory Flexibility Analysis, as required under the
Regulatory Flexibility Act, can be found in the Regulatory Impact
Analysis discussed below.
    We have developed a comprehensive Regulatory Impact Analysis that
assesses the impacts of the document. The full analysis of economic
impacts is available in Docket No. FDA-2016-N-0124 (Ref. 51) and at
https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

VIII. Paperwork Reduction Act of 1995

    This document contains no collection of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 is not required.

IX. Analysis of Environmental Impact

    We have determined under 21 CFR 25.31(a) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

X. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this document in accordance with the principles
set forth in Executive Order 13175. We have determined that the
document does not contain policies that have substantial direct effects
on one or more Indian Tribes, on the relationship between the Federal
Government and Indian Tribes, or on the distribution of power and
responsibilities between the Federal Government and Indian Tribes.
Accordingly, we conclude that the document does not contain policies
that have tribal implications as defined in the Executive Order and,
consequently, a tribal summary impact statement is not required.

XI. Federalism

    We have analyzed this document in accordance with the principles
set forth in Executive Order 13132. Section 4(a) of the Executive order
requires agencies to ``construe . . . a Federal statute to preempt
State law only where the statute contains an express preemption
provision or there is some other clear evidence that the Congress
intended preemption of State law, or where the exercise of State
authority conflicts with the exercise of Federal authority under the
Federal statute.'' The sole statutory provision giving preemptive
effect to the document is section 751 of the FD&C Act (21 U.S.C. 379r).
We have complied with all of the applicable requirements under the
Executive order and have

determined that the preemptive effects of this document are consistent
with Executive Order 13132.

XII. References

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

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* 2. Comment submitted in Docket No. FDA-1975-N-0012-0081. Available
at https://www.regulations.gov/document?D=FDA-1975-N-0012-0081.
* 3. Transcript of the March 23, 2005, Nonprescription Drugs
Advisory Committee. Available at http://wayback.archive-it.org/7993/20170404055944/https://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4098T1.htm.
* 4. Transcript of the October 20, 2005, Meeting of the
Nonprescription Drugs Advisory Committee. Available at http://wayback.archive-it.org/7993/20170404055923/https://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4184T1.pdf.
* 5. Summary Minutes of the November 14, 2008, Feedback Meeting with
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