[Federal Register Volume 82, Number 243 (Wednesday, December 20, 2017)]
[Rules and Regulations]
[Pages 60474-60503]
[FR Doc No: 2017-27317]

Vol. 82

Wednesday,

No. 243

December 20, 2017

Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 310

Safety and Effectiveness of Health Care Antiseptics; Topical
Antimicrobial Drug Products for Over-the-Counter Human Use; Final Rule

Federal Register / Vol. 82 , No. 243 / Wednesday, December 20, 2017 /
Rules and Regulations

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2015-N-0101]
RIN 0910-AH40

Safety and Effectiveness of Health Care Antiseptics; Topical
Antimicrobial Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing this final rule establishing that certain active ingredients
used in nonprescription (also known as over-the-counter or OTC)
antiseptic products intended for use by health care professionals in a
hospital setting or other health care situations outside the hospital
are not generally recognized as safe and effective (GRAS/GRAE). FDA is
issuing this final rule 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 health care antiseptic products that have come to the Agency's
attention. This final rule finalizes the 1994 tentative final monograph
(TFM) for OTC health care antiseptic 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 May 1, 2015
(2015 Health Care Antiseptic Proposed Rule (PR)).

DATES: This rule is effective December 20, 2018.

ADDRESSES: For access to the docket to read background documents or the
electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number found in brackets in
the heading of this 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: Michelle M. Jackson, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5420, Silver Spring, MD 20993-0002, 301-
796-0923.

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 and Acronyms Commonly Used in This
Document
III. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Final Rule Covers Only Health Care Antiseptics
IV. Background
    A. Significant Rulemakings Relevant to This Final Rule
    B. Public Meetings Relevant to This Final Rule
    C. Scope of This Final Rule
    D. Eligibility for the OTC Drug Review
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. General Comments on the Proposed Rule and FDA Response
    C. Comments on Eligibility of Active Ingredients and FDA
Response
    D. Comments on Effectiveness and FDA Response
    E. Comments on Safety and FDA Response
    F. Comments on the Preliminary Regulatory Impact Analysis and
FDA Response
VI. Ingredients Not Generally Recognized as Safe and Effective
VII. Compliance Date
VIII. Summary of Regulatory Impact Analysis
    A. Introduction
    B. Summary of Costs and Benefits
IX. Paperwork Reduction Act of 1995
X. Analysis of Environmental Impact
XI. Federalism
XII. References

I. Executive Summary

A. Purpose of the Final Rule

    This final rule finalizes the 2015 Health Care Antiseptic PR. This
final rule applies to health care antiseptic products that are intended
for use by health care professionals in a hospital setting or other
health care situations outside the hospital. Health care antiseptic
products include health care personnel hand washes, health care
personnel hand rubs, surgical hand scrubs, surgical hand rubs, and
patient antiseptic skin preparations (i.e., patient preoperative and
preinjection skin preparations).
    In response to several requests submitted to the 2015 Health Care
Antiseptic PR, FDA has deferred further rulemaking on six active
ingredients used in OTC health care antiseptic 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, benzethonium chloride,
chloroxylenol, alcohol (also referred to as ethanol or ethyl alcohol),
isopropyl alcohol, and povidone-iodine. Accordingly, FDA does not make
a GRAS/GRAE determination in this final rule for these six active
ingredients for use as OTC health care antiseptics. The monograph or
nonmonograph status of these six ingredients will be addressed, either
after completion and analysis of ongoing studies to address the safety
and effectiveness data gaps of these ingredients or at a later date, if
these studies are not completed.
    This rulemaking finalizes the nonmonograph status of the remaining
24 active ingredients intended for use in health care antiseptics
identified in the 2015 Health Care Antiseptic PR. No additional data
were submitted to support monograph conditions for these 24 health care
antiseptic active ingredients. Therefore, this rule finalizes the 2015
Health Care Antiseptic PR and finds that 24 health care antiseptic
active ingredients are not GRAS/GRAE for use as OTC health care
antiseptics. Accordingly, OTC health care antiseptic drugs containing
any of these 24 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 314) of the regulations are
required for marketing and may be misbranded under section 502 of the
FD&C Act (21 U.S.C. 352).
    This final rule covers only OTC health care antiseptics that are
intended for use by health care professionals in a hospital setting or
other health care situations outside the hospital. This final rule does
not cover consumer antiseptic washes (78 FR 76444, 81 FR 61106);
consumer antiseptic rubs (81 FR 42912); 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

1. Safety
    Several important scientific developments that affect the safety
evaluation of OTC health care antiseptic active ingredients have
occurred since FDA's 1994 safety evaluation. Improved analytical
methods now exist that can detect and more accurately measure these
active ingredients at lower levels in the bloodstream and tissue.
Consequently, new data suggest that the

systemic exposure to these active ingredients is higher than previously
thought, and new information about the potential risks from systemic
absorption and long-term exposure is now available. New safety
information also suggests that widespread antiseptic use could have an
impact on the development of bacterial resistance. To support a
classification of generally recognized as safe (GRAS) for health care
antiseptic active ingredients, we proposed that additional data were
needed to demonstrate that those ingredients meet current safety
standards (80 FR 25166 at 25179 to 25195).
    The minimum data needed to demonstrate safety for all health care
antiseptic active ingredients fall into four broad categories: (1)
Human safety studies described in current FDA guidance (e.g., maximal
usage trial or ``MUsT''); (2) nonclinical safety studies described in
current FDA guidance (e.g., developmental and reproductive toxicity
studies and carcinogenicity studies); (3) data to characterize
potential hormonal effects; and (4) data to evaluate the development of
antimicrobial resistance.
    We have considered the recommendations from the public meetings
held by the Agency on antiseptics (see section IV.B, table 2) and
evaluated the available literature, as well as the data, the comments,
and other information that were submitted to the rulemaking on the
safety of the 24 non-deferred health care antiseptic active ingredients
addressed in this final rule. The available information and published
data for these 24 active ingredients considered in this final rule are
insufficient to establish the safety of these active ingredients for
use in health care antiseptic products. No additional data were
provided for these 24 ingredients. Consequently, the available data do
not support a GRAS determination for the OTC non-deferred health care
antiseptic active ingredients addressed in this final rule.
2. Effectiveness
    A determination that an active ingredient is GRAS/GRAE for a
particular intended use requires a benefit-to-risk assessment for the
drug for that use. New information on potential risks posed by the
increased use of certain health care antiseptics in clinical practice,
as well as input from the 2005 NDAC, prompted us to reevaluate the data
needed to determine whether health care antiseptic active ingredients
are generally recognized as effective (GRAE). We continued to propose
the use of surrogate endpoints (bacterial log reductions) as a
demonstration of effectiveness for health care antiseptics combined
with in vitro testing to characterize the antimicrobial activity of the
active ingredient (80 FR 25166).
    We have considered the recommendations from the public meetings
held by the Agency on antiseptics (see section IV.B, table 2) and
evaluated the available literature, as well as the data, the comments,
and other information that were submitted to the rulemaking on the
effectiveness of the 24 non-deferred health care antiseptic active
ingredients addressed in this final rule. Since the publication of the
2015 Health Care Antiseptic PR, no new data or information was
submitted on the effectiveness of these 24 non-deferred health care
antiseptic active ingredients. Consequently, there is insufficient data
to support a GRAE determination for these ingredients.

C. Costs and Benefits

    This rule establishes that 24 eligible active ingredients are not
generally recognized as safe and effective for use in nonprescription
(also referred to as over-the-counter or OTC) health care antiseptics.
However, data from the FDA drug product registration database suggest
that only one of these 24 ingredients is found in OTC health care
antiseptic products currently marketed pursuant to the TFM: Triclosan.
Regulatory action is being deferred on six active ingredients that were
included in the health care antiseptic proposed rule: Benzalkonium
chloride, benzethonium chloride, chloroxylenol, ethyl alcohol,
isopropyl alcohol, and povidone-iodine. This final rule also addresses
comments on the eligibility of three active ingredients--alcohol (ethyl
alcohol), benzethonium chloride, and chlorhexidine gluconate--and finds
that these three active ingredients are ineligible for evaluation under
the OTC Drug Review for certain health care antiseptic uses because
these active ingredients were not included in health care antiseptic
products marketed for the specified indications prior to May 1972. To
our knowledge, there is only one ineligible product currently on the
market, an alcohol-containing surgical hand scrub, which is affected by
this rule.
    Benefits are quantified as the volume reduction in exposure to
triclosan found in health care antiseptic products affected by the
rule, but these benefits are not monetized. Annual benefits are
estimated to be a reduction in exposure of 88,000 kilograms (kg) of
triclosan per year.
    Costs are calculated as the one-time costs associated with
reformulating health care antiseptic products containing the active
ingredient triclosan and relabeling reformulated products. We believe
that the alcohol-containing surgical hand scrub that is affected by
this rule is likely to be removed from the market. We categorize the
associated loss of sales revenue as a transfer from one manufacturer to
another and not a cost, because we assume that the supply of other,
highly substitutable, products is highly elastic.
    Annualizing the one-time costs over a 10-year period, we estimate
total annualized costs to range from $1.1 to $4.1 million at a 3
percent discount rate, and from $1.2 to $4.7 million at a 7 percent
discount rate. The present value of total costs ranges from $9.0 to
$34.6 million at a 3 percent discount rate, and from $8.7 to $29.6
million at a 7 percent discount rate.
    In this final rule, small entities will bear costs to the extent
that they must reformulate and re-label any health care antiseptic
containing triclosan that they produce. The average cost to small firms
of implementing the requirements of this final rule is estimated to be
$213,176 per firm. The costs of the changes, along with the small
number of firms affected, implies that this burden would not be
significant, so we certify that this final rule will not have a
significant economic impact on a substantial number of small entities.
This analysis, together with other relevant sections of this document,
serves as the Regulatory Flexibility Analysis, as required under the
Regulatory Flexibility Act.
    The full discussion of economic impacts is available in docket FDA-
2015-N-0101 and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

[GRAPHIC] [TIFF OMITTED] TR20DE17.000

                                       Executive Order 13771 Summary Table
                           [In $ millions 2016 dollars, over an infinite time horizon]
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                                                                                Lower bound     Upper bound
                                                                   Primary (7%)        (7%)            (7%)
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Present Value of Costs..........................................          $17.19           $8.68          $29.47
Present Value of Cost Savings...................................  ..............  ..............  ..............
Present Value of Net Costs......................................           17.19            8.68           29.47
Annualized Costs................................................            1.20            0.61            2.06
Annualized Cost Savings.........................................  ..............  ..............  ..............
Annualized Net Costs............................................            1.20            0.61            2.06
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II. Table of Abbreviations and Acronyms Commonly Used in This Document

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         Abbreviation                        What it means
------------------------------------------------------------------------
ADME.........................  Absorption, distribution, metabolism, and
                                excretion.
ANPR.........................  Advance notice of proposed rulemaking.
APA..........................  Administrative Procedure Act.
ASTM.........................  American Society for Testing and
                                Materials International.
ATCC.........................  American Type Culture Collection.
ATE..........................  Average Treatment Effect.
CDC..........................  Centers for Disease Control and
                                Prevention.
CFR..........................  Code of Federal Regulations.

DART.........................  Developmental and reproductive toxicity.
FDA..........................  Food and Drug Administration.
FD&C Act.....................  Federal Food, Drug, and Cosmetic Act.
FR...........................  Federal Register.
GRAE.........................  Generally recognized as effective.
GRAS.........................  Generally recognized as safe.
ICH..........................  International Council for Harmonisation
                                of Technical Requirements for
                                Pharmaceuticals for Human Use.
MBC..........................  Minimum bactericidal concentration.
MIC..........................  Minimum inhibitory concentration.
MusT.........................  Maximal usage trial.
NCE..........................  New chemical entity.
NDA..........................  New drug application.
NDAC.........................  Nonprescription Drugs Advisory Committee.
NHS..........................  Nurses' Health Study.
NIH..........................  National Institutes of Health.
NOAEL........................  No observed adverse effect level.
OMB..........................  Office of Management and Budget.
OTC..........................  Over-the-counter.
PBPK.........................  Physiologically-based pharmacokinetic.
PK...........................  Pharmacokinetic.
PR...........................  Proposed rule.
TFM..........................  Tentative final monograph.
U.S.C........................  United States Code.
USP..........................  United States Pharmacopeia.
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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 health care antiseptic active ingredients that are the subject
of this final rule.

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 advance notice of proposed
rulemaking (ANPR) that was published in the Federal Register of
September 13, 1974 (39 FR 33103) (the 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) (the 1978 TFM); the Federal Register of June 17, 1994 (59 FR
31402) (the 1994 TFM); and the Federal Register of May 1, 2015 (80 FR
25166) (the 2015 Health Care Antiseptic PR), 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 safe and effective, and further testing is required).
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 this 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

    The OTC topical antimicrobial rulemaking has had a broad scope,
encompassing drug products that may contain the same active
ingredients, but that are labeled and marketed for different intended
uses. The 1974 ANPR for topical antimicrobial products encompassed
products for both health care and consumer use (39 FR 33103). The 1974
ANPR covered seven different intended uses for these products: (1)
Antimicrobial soap; (2) health care 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 antiseptics.'' 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 final rule does not have an impact on 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) health care
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). In
section V.B.5, we address comments filed in this rulemaking on
antiseptics for use by the food industry, but we do not otherwise
discuss these antiseptics in this document. This final rule does not
have an impact on the status of antiseptics for food industry use.
    The 1994 TFM did not distinguish between consumer antiseptic washes
and rubs and health care antiseptic washes and rubs. In the 2013
Consumer Wash PR, we proposed that our evaluation of OTC antiseptic
drug products be further subdivided into health care 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 Wash PR (78 FR 76444 at 76446 to 76447) and the 2016 Consumer
Rub PR (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 final rule does not have an impact on the status of consumer
antiseptic wash or consumer antiseptic rub products.

C. This Final Rule Covers Only Health Care Antiseptics

    We refer to the group of products covered by this final rule as
``health care antiseptics.'' Health care antiseptics are drug products
that are generally intended for use by health care professionals in a
hospital setting or other health care situations outside the hospital.
Patient antiseptic skin preparations, which are products that are used
for preparation of the skin prior to surgery (i.e., preoperative) and
preparation of skin prior to an injection (i.e., preinjection), may be
used by patients outside the traditional health care setting. Some
patients (e.g., diabetics who manage their disease with insulin
injections) self-inject medications that have been prescribed by a
health care professional for use at home or at other locations and use
patient preoperative skin preparations prior to injection.
    In this final rule, we use the term ``health care antiseptics'' to
include the following products:

 Health care personnel hand washes
 Health care personnel hand rubs
 Surgical hand scrubs
 Surgical hand rubs
 Patient antiseptic skin preparations (i.e., patient
preoperative and preinjection skin preparations) \1\
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    \1\ Because the category of products referred to as ``patient
preoperative skin preparations'' in the 1994 TFM and the 2015 Health
Care Antiseptic PR encompasses products that are used for
preinjection skin preparation in health care settings outside the
hospital (so not preoperative), in this final rule we refer to such
products as ``patient antiseptic skin preparations.''
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    This final rule covers health care antiseptic products that are
rubs and others that are washes. The 1994 TFM did not distinguish
between products that we are now calling health care ``antiseptic
washes'' and products we are now calling health care ``antiseptic
rubs.'' Washes are rinsed off with water, and include health care
personnel hand washes and surgical hand scrubs. Rubs are sometimes
referred to as ``leave-on products'' and are not rinsed off after use.
Rubs include health care personnel hand rubs, surgical hand rubs, and
patient antiseptic skin preparations.
    Completion of the monograph for health care antiseptic products and
certain other monographs for the active ingredient triclosan is 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 rulemaking and discuss our response to
comments received on the 2015 Health Care Antiseptic PR.

A. Significant Rulemakings Relevant to This Final Rule

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

   Table 1--Significant Rulemaking Publications Related to Health Care
                      Antiseptic Drug Products \1\
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     Federal Register  notice               Information in notice
------------------------------------------------------------------------
1974 ANPR (September 13, 1974, 39   We published an ANPR to establish a
 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 (January 6,  We published our tentative
 1978, 43 FR 1210).                  conclusions and proposed
                                     effectiveness testing for 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, 1991,  We amended the 1978 TFM to establish
 56 FR 33644).                       a 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 Healthcare Antiseptic TFM      We amended the 1978 TFM to establish
 (June 17, 1994, 59 FR 31402).       a separate monograph for the group
                                     of products referred to as OTC
                                     topical health care antiseptic drug
                                     products. These antiseptics are
                                     generally intended for use by
                                     health care 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 TFM   We issued a proposed rule to amend
 (December 17, 2013, 78 FR 76444).   the 1994 TFM and to establish data
                                     standards 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 TFM     We issued a proposed rule to amend
 (May 1, 2015, 80 FR 25166).         the 1994 TFM and to establish data
                                     standards for determining whether
                                     OTC health care 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 health
                                     care antiseptic active ingredients.
2016 Consumer Antiseptic Rub TFM    We issued a proposed rule to amend
 (June 30, 2016, 81 FR 42912).       the 1994 TFM and to establish data
                                     standards 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 6,       certain active ingredients used in
 2016, 81 FR 61106).                 OTC 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.
------------------------------------------------------------------------
\1\ The publications listed in table 1 can be found at FDA's ``Status of
  OTC Rulemakings'' website available at http://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 Final Rule

    In addition to the Federal Register publications listed in table 1,
there have been three meetings of the NDAC that are relevant to the
discussion of health care antiseptic safety and effectiveness. These
meetings are summarized in table 2.

      Table 2--Public Meetings Relevant to Health Care Antiseptics
------------------------------------------------------------------------
        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 health care 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 health
                                          care antiseptics (Ref. 3).
September 2014, NDAC Meeting (July 29,   Safety testing framework for
 2014, 79 FR 44042).                      health care antiseptic active
                                          ingredients (Ref. 4).
------------------------------------------------------------------------

C. Scope of This Final Rule

    This rulemaking finalizes the nonmonograph status of the 24 listed
health care antiseptic active ingredients (see section IV.D.1).
Requests were made that benzalkonium chloride, benzethonium chloride,
chloroxylenol, alcohol, isopropyl alcohol, and povidone-iodine be
deferred from consideration in this health care antiseptic final rule
to allow more time for interested parties to complete the studies
necessary to fill the safety and effectiveness data gaps identified in
the 2015 Health Care Antiseptic PR for these ingredients. In January
2017, we agreed to defer rulemaking on these six ingredients (see
Docket No. 2015-N-0101 at https://www.regulations.gov).
    For the 24 active ingredients included in this final rule, no
additional data were submitted to the record to fill the safety and
effectiveness data gaps identified in the 2015 Health Care Antiseptic
PR for these 24 active ingredients. Therefore, we find that these 24
active ingredients are not GRAS/GRAE for use in health care antiseptic
drug products and these ingredients are not included in the OTC topical
antiseptic monograph at this time. Products containing these
ingredients are new drugs for which approved new drug applications
(NDAs) or abbreviated new drug applications (ANDAs) are required prior
to marketing. Accordingly, FDA is amending part 310 (21 CFR part 310)
to add the active ingredients covered by this final rule to the list of
active ingredients in Sec.  310.545 (21 CFR 310.545) that are not GRAS/
GRAE for use in the specified OTC drug products.

D. 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) (Ref. 5).\2\ 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 Sec.
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. Ineligibility for use as a health care
antiseptic does not affect eligibility under any other OTC drug
monograph.
---------------------------------------------------------------------------

    \2\ 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 in the OTC monograph
system based on submission of a time and extent application. (See
Sec.  330.14.)
---------------------------------------------------------------------------

1. Eligible Active Ingredients
    Table 3 lists the health care antiseptic active ingredients that
have been considered under this rulemaking and shows whether each
ingredient is eligible or ineligible for evaluation under the OTC Drug
Review for use in health care antiseptics for each of the five
specified uses: Patient antiseptic skin preparation, health care
personnel hand wash, health care personnel hand rub, surgical hand
scrub, and surgical hand rub.

                                Table 3--Eligibility of Antiseptic Active Ingredients for Health Care Antiseptic Uses \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Patient           Health care         Health care
                  Active ingredient                    antiseptic  skin     personnel  hand     personnel  hand     Surgical  hand    Surgical  hand rub
                                                          preparation            wash                 rub                scrub
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol 60 to 95 percent............................              \2\ Y               \3\ N                   Y                   N                   Y
Benzalkonium chloride...............................                  Y                   Y                   Y                   Y                   N
Benzethonium chloride...............................                  Y                   Y                   N                   Y                   N
Chlorhexidine gluconate.............................                  N                   N                   N                   N                   N
Chloroxylenol.......................................                  Y                   Y                   N                   Y                   N
Cloflucarban........................................                  Y                   Y                   N                   Y                   N
Fluorosalan.........................................                  Y                   Y                   N                   Y                   N
Hexylresorcinol.....................................                  Y                   Y                   N                   Y                   N
Iodine complex (ammonium ether sulfate and                            N                   Y                   N                   Y                   N
 polyoxyethylene sorbitan monolaurate)..............
Iodine complex (phosphate ester of alkylaryloxy                       Y                   Y                   N                   Y                   N
 polyethylene glycol)...............................
Iodine tincture United States Pharmacopeia (USP)....                  Y                   N                   N                   N                   N
Iodine topical solution USP.........................                  Y                   N                   N                   N                   N
Nonylphenoxypoly (ethyleneoxy) ethanoliodine........                  Y                   Y                   N                   Y                   N
Poloxamer-iodine complex............................                  Y                   Y                   N                   Y                   N
Povidone-iodine 5 to 10 percent.....................                  Y                   Y                   N                   Y                   N
Undecoylium chloride iodine complex.................                  Y                   Y                   N                   Y                   N
Isopropyl alcohol 70-91.3 percent...................                  Y                   N                   Y                   N                   Y
Mercufenol chloride.................................                  Y                   N                   N                   N                   N
Methylbenzethonium chloride.........................                  Y                   Y                   N                   Y                   N
Phenol (equal to or less than 1.5 percent)..........                  Y                   Y                   N                   Y                   N
Phenol (greater than 1.5 percent)...................                  Y                   Y                   N                   Y                   N
Secondary amyltricresols............................                  Y                   Y                   N                   Y                   N
Sodium oxychlorosene................................                  Y                   Y                   N                   Y                   N
Triclocarban........................................                  Y                   Y                   N                   Y                   N
Triclosan...........................................                  Y                   Y                   N                   Y                   N
Combinations:
    Calomel, oxyquinoline benzoate, triethanolamine,                  Y                   N                   N                   N                   N
     and phenol derivative..........................
    Mercufenol chloride and secondary amyltricresols                  Y                   N                   N                   N                   N
     in 50 percent alcohol..........................
    Triple dye......................................                  Y                   N                   N                   N                   N
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Hexachlorophene and tribromsalan are not included in this table because they are the subject of final regulatory action (see section IV.D.3).
\2\ Y = Eligible for specified use.
\3\ N = Ineligible for specified use.

2. Ineligible Active Ingredients
    In the 2015 Health Care Antiseptic PR (and as outlined in table 3),
we identified certain active ingredients that were considered
ineligible for evaluation under the OTC Drug Review as a health care
antiseptic for specific indications. We noted, however, that if the
requested documentation for eligibility was submitted, these active
ingredients could be determined to be eligible for evaluation (80 FR
25166 at 25171).
    We received a comment requesting that benzethonium chloride be
deemed eligible for evaluation under the OTC Drug Review for use as a
health care personnel hand rub and surgical hand rub. For the reasons
explained in section V.C.1, we find that benzethonium chloride
continues to be ineligible for evaluation under the OTC Drug Review for
use as a health care personnel hand rub and surgical hand rub.
Consequently, drug products containing benzethonium chloride for use in
health care personnel hand rubs and surgical hand rubs will require
approval under an NDA or ANDA prior to marketing.
    We also received comments arguing that chlorhexidine gluconate is
eligible for evaluation under the OTC Drug Review for use as a health
care antiseptic. For the reasons explained in section V.C.2, we find
that chlorhexidine gluconate continues to be ineligible for evaluation
under the OTC Drug Review for use as a health care antiseptic.
Consequently, drug products containing chlorhexidine gluconate for use
in health care antiseptics will require approval under an NDA or ANDA
prior to marketing.
    In addition, we received a comment requesting that alcohol be
deemed eligible for evaluation under the OTC Drug Review for use as a
surgical hand scrub. For the reasons explained in section V.C.3, we
find that alcohol continues to be ineligible for evaluation under the
OTC Drug Review for use as a surgical hand scrub. Consequently, drug
products containing alcohol for use in surgical hand scrubs will
require approval under an NDA or ANDA prior to marketing.
    Moreover, for the remaining health care antiseptic active
ingredients that we proposed were ineligible for evaluation under the
OTC Drug Review, we have not received any new information since the
publication of the 2015 Health Care Antiseptic PR demonstrating that
these ineligible active ingredients are eligible for

evaluation under the OTC Drug Review for use as a health care
antiseptic for the specified indications (see table 3). Consequently,
we find that these active ingredients continue to be ineligible for
evaluation under the OTC Drug Review for use as a health care
antiseptic for the specified indications and drug products containing
these ineligible active ingredients will require approval under an NDA
or ANDA prior to marketing.
3. Ingredients Previously Proposed as Not Generally Recognized as Safe
and Effective
    FDA may determine that an active ingredient is not GRAS/GRAE for a
given OTC use (i.e., nonmonograph) because of lack of evidence of
effectiveness, lack of evidence of safety, or both. In the 1994 TFM (59
FR 31402 at 31435 to 31436) and the 2015 Health Care Antiseptic PR (80
FR 25166 at 25173 to 25174), FDA proposed that the active ingredients
fluorosalan, hexachlorophene, phenol (greater than 1.5 percent), and
tribromsalan be found not GRAS/GRAE for the uses set forth in the 1994
TFM: Antiseptic hand wash, health care personnel hand wash, patient
antiseptic skin preparation, and surgical hand scrub. FDA did not
classify hexachlorophene or tribromsalan in the 1978 TFM (43 FR 1210 at
1227) because it had already taken final regulatory action against
hexachlorophene (21 CFR 250.250) and certain halogenated salicylamides,
notably tribromsalan (21 CFR 310.502). No substantive comments or new
data were submitted to the record of the 1994 TFM or the 2015 Health
Care Antiseptic PR to support reclassification of any of these
ingredients as GRAS/GRAE. Therefore, FDA has determined that these
active ingredients are not GRAS/GRAE for use in OTC health care
antiseptic products as defined in this final rule, and drug products
containing these ineligible active ingredients will require approval
under an NDA or ANDA prior to marketing.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    In response to the 2015 Health Care Antiseptic PR, we received
approximately 29 comments from drug manufacturers, trade associations,
academia, testing laboratories, health professionals, and individuals.
We also received additional data and information for certain deferred
health care antiseptic active ingredients.
    We describe and respond to the comments in section V.B through V.F.
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. Effective Date
    (Comment 1) Several comments requested that FDA extend its timeline
under the 2015 Health Care Antiseptic PR to allow more time for the
submission of new data and information. They asserted that the one year
compliance date was too short and that it could take several years to
design, execute, analyze, and report on the necessary safety and
effectiveness studies.
    (Response 1) In the 2015 Health Care Antiseptic PR, we provided a
process for seeking an extension of time to submit the required safety
and effectiveness data if such an extension is necessary (80 FR 25166
at 25169). As explained in the proposed rule, we stated that we would
consider all the data and information submitted to the record in
conjunction with all timely and completed requests to extend the
timeline to finalize the monograph status for a given ingredient. We
received requests to defer six health care antiseptic active
ingredients from this rulemaking. Consideration for deferral for an
ingredient was given to requests with clear statements of intent to
conduct the necessary studies required to fill all the data gaps
identified in the proposed rule for that ingredient. After analyzing
the data and information submitted related to the requests for
extensions, we determined that a deferral is warranted for the six
health care antiseptic active ingredients--benzalkonium chloride,
benzethonium chloride, chloroxylenol, alcohol, isopropyl alcohol, and
povidone-iodine--to allow more time for interested parties to complete
the studies necessary to fill the safety and effectiveness data gaps
identified for these ingredients in the 2015 Health Care Antiseptic PR.
The monograph status of these six ingredients will be addressed either
after completion and analysis of ongoing studies to address the safety
and effectiveness data gaps of these ingredients or at a later date if
these studies are not completed. We did not receive any deferral
requests for the 24 remaining health care antiseptic active
ingredients, and so we decline to defer final action on the proposed
rule for these ingredients.
2. Use in Health Care Settings Outside the Hospital
    (Comment 2) One comment requested that FDA ``better clarify and
define the scope'' of this rulemaking on the use of health care
antiseptics in health care settings outside of the hospital ``in order
that the proper antiseptic products are provided for patients in the
spectrum of health care settings while also being covered by health
care insurers.'' The comment stated that patients and health care
workers in these other settings deserve the same level of safety and
efficacy standards as those in the hospital setting. The comment
expressed concern that certain entities may determine that they need to
supply products intended for ``consumer use,'' which, the comment
stated, may have different and lesser standards.
    (Response 2) We agree that health care antiseptic products are used
in a variety of health care settings, not just hospitals. Over the past
several decades, there has been a significant shift in health care
delivery from the acute, inpatient hospital setting to a variety of
outpatient and community-based settings. There are many examples of
health care settings outside the hospital that involve the use of
antiseptic products. These settings include, but are not limited to,
the care of patients in outpatient medical and surgical facilities,
dental clinics, skilled nursing facilities or nursing homes, adult
medical day care centers, public health clinics, imaging centers,
oncology clinics, infusion centers, dialysis centers, behavioral health
clinics, physical therapy and rehabilitation centers, and in private
homes. The term ``health care'' as used in this rulemaking includes all
these settings.
    We note, however, that this rule does not address the use of a
specific health care antiseptic drug product in a particular health
care situation. In addition, the coverage of antiseptic drug products
by health care insurers is outside FDA's purview.
3. GRAS/GRAE Classification of Certain Ingredients
    (Comment 3) Several comments requested that FDA reconsider its
proposal in the 2015 Health Care Antiseptic PR to classify alcohol,
isopropyl alcohol, and povidone-iodine as Category III active
ingredients. In the 1994 TFM, alcohol, isopropyl alcohol,

and povidone-iodine were proposed to be classified as Category I
topical antiseptic ingredients for certain indications. The comments
contended that FDA's proposal to change these ingredients' proposed
classification from Category I to Category III is not based on a safety
or effectiveness concern or issue. One comment noted that during the
September 3, 2014, NDAC meeting, several NDAC members expressed
concerns about changing the proposed classification of alcohol,
isopropyl alcohol, and povidone-iodine from Category I to Category III,
indicating that the change in the proposed classification could lead
health care personnel to stop using products with these active
ingredients. The comment also pointed out that, in the 2015 Health Care
Antiseptic PR and in related public announcements, FDA emphasized that
we did not believe that health care antiseptic products containing
these ingredients were ineffective or unsafe, or that their use should
be discontinued. In fact, that comment noted that FDA recommended that
health care personnel continue to use these antiseptic products
consistent with infection control guidelines while additional data
about the products were gathered.
    (Response 3) As we explained in the 2015 Heath Care Antiseptic PR,
the OTC drug procedural 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 safe and effective, and further testing is
required) (80 FR 25166 at 25168). We classify ingredients as Category
I, II, or 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. In the
1994 TFM, alcohol and povidone-iodine were both proposed to be
classified as Category I topical antiseptic ingredients for use in
surgical hand scrubs, patient antiseptic skin preparations, and
antiseptic hand washes or health care personnel hand wash products (59
FR 31402 at 31420 and 31433). Isopropyl alcohol was proposed to be
classified as Category I for patient antiseptic skin preparation ``for
the preparation of the skin prior to an injection'' (59 FR 31402 at
31433).
    In the 2015 Health Care Antiseptic PR, we changed the proposed
classification of alcohol, isopropyl alcohol, and povidone-iodine from
Category I to III for these indications, because we found that there
was not enough data on these three ingredients to meet our proposed
safety and effectiveness data requirements. We explained that we were
proposing changes to the safety and effectiveness data requirements
identified in the 1994 TFM in light of comments we received, input from
subsequent public meetings, and our independent evaluation of other
relevant scientific information (80 FR 25166 at 25166).
    Among other things, our proposed revisions to the data requirements
identified in the 1994 TFM were based on several important scientific
developments that affected the safety evaluation of health care
antiseptic active ingredients, including improved analytical methods
that can detect and more accurately measure these ingredients at lower
levels in the bloodstream and tissue (80 FR 25166 at 25166 to 25167).
As a result of these improved methods, we have learned that some
systemic exposures can be detected, where previously they were
undetected, and that some systemic exposures are higher than previously
thought. We also have new information about the potential risks from
systemic absorption and long-term exposure (80 FR 25166 at 25167). In
addition, the standard battery of tests that were used to determine the
safety of drugs had changed over time to incorporate improvements in
safety testing. As we explained in the 2015 Health Care Antiseptic PR,
it is critical that the safety and effectiveness of these ingredients
be supported by data that meet the most current standards, considering
the prevalent use of health care antiseptic products (80 FR 25166 at
25167).
    Our decision to propose revising the safety and effectiveness data
requirements identified in the 1994 TFM was also based in part on
meetings of the NDAC that were held in March 2005 and September 2014.
As we noted in the preamble to the 2015 Health Care Antiseptic PR,
input from participants at the March 2005 NDAC meeting prompted us to
reevaluate the data needed for classifying health care antiseptic
active ingredients as GRAE (80 FR 25166 at 25166). Moreover, at the
meeting held in September 2014, the NDAC discussed FDA's proposed
revisions to the safety data requirements and unanimously voted that
the revised safety data requirements were appropriate to demonstrate
that a health care antiseptic active ingredient is GRAS.
    As one comment noted, at the September 2014 meeting, several NDAC
members expressed concerns about changing the proposed classification
of alcohol, isopropyl alcohol, and povidone-iodine from Category I to
Category III, indicating that this change in the proposed
classification could lead health care personnel to stop using products
with these active ingredients. At the same meeting, FDA emphasized both
that health care antiseptics are a critically important part of the
infection control paradigm in place in every hospital across the
country and that our goal is not to remove such products from the
market (Ref. 4). That remains our goal, and we note that these
ingredients have each been deferred, so they are not addressed in this
final rule.
4. Patient Preoperative Skin Preparation
    (Comment 4) One comment asked FDA to clarify the term ``patient
preoperative skin preparation,'' noting that, in the 2015 Health Care
Antiseptic PR, the term ``patient preoperative skin preparation''
includes skin preparation prior to an injection (preinjection) and that
this may cause confusion because it could be misinterpreted to mean
that all products listed can be used for either patient preoperative
skin preparation or preinjection.
    Several comments also asserted that the effectiveness testing for
preinjection should have different clinically relevant time points
because preinjection use serves a different purpose and has a different
use pattern than patient preoperative skin preparations. They argued
that surgical incision demands persistent activity due to the invasive
nature of cutting through the skin's natural barrier over a larger
area, the procedure duration (which can be hours), and the time the
incision point will be open and will subsequently need to heal. As
such, the comments argued, persistence may be an important attribute of
patient preoperative skin preparations. They explained that in
contrast, an injection is a procedure lasting only seconds and poses a
relatively low risk of infection. They also explained that the
injection site heals quickly, so there is no need for persistent
antimicrobial activity. They stated that if patient preinjection skin
preparation products are required to meet the same effectiveness
requirements as patient preoperative skin preparation products, this
would effectively clear the market of available cost effective
solutions for those who need these products. Therefore, the comments
asserted that the effectiveness requirements for patient preoperative
skin preparation should be different from the effectiveness
requirements for patient preinjection skin preparations.
    (Response 4) We agree that the circumstances under which health
care

antiseptics can be used for preinjection should be clarified because
patient preoperative skin preparations and preinjection skin
preparations can serve different purposes and have different uses.
Accordingly, we clarify that patient preoperative skin preparation and
patient preinjection skin preparation may involve separate uses within
the category of patient antiseptic skin preparations. As noted in the
comments, surgical incisions require persistent activity from patient
preoperative skin preparations due to the invasive nature of cutting
through the skin's natural barrier over a larger area, the procedure
duration (which can be hours), and the time the incision point will be
open and will subsequently need to heal. As such, persistence is an
important attribute of patient preoperative skin preparations. In
comparison, injection refers to a brief interruption of skin integrity
by a sterile needle that is typically removed within seconds or a few
minutes. Due to the brevity of the procedure, the risk of bacterial
infection from an injection is low, and so persistent antimicrobial
activity is not essential for a preinjection skin preparation product.
    Examples of procedures that are covered by a preinjection claim
include the following:

 Intramuscular injection for vaccination
 Intramuscular injection for delivery of medication, such as an
antibiotic or an anesthetic (for trigger point injection)
 Intradermal injection for tuberculin testing
 Subcutaneous injection of insulin
 Subcutaneous placement of needles for acupuncture
 Venipuncture for blood drawing for laboratory testing
 Intradermal injection for allergy skin testing

    Examples of procedures that are not covered by the preinjection
claim include the following:

 Venous catheterization for blood donation
 Venous catheterization for an extended delivery of medication,
such as slow infusion of an antibiotic
 Venous catheterization for delivery of intravenous fluid
 Placement of a central venous catheter for any purpose
 Placement of a heparin lock
 Placement of an arterial catheter
 Surgical procedure

    As stated in the 2015 Health Care Antiseptic PR (80 FR 25166 at
25176), the effectiveness criteria for health care antiseptics are
based on the premise that bacterial reductions achieved using tests
that simulate conditions of actual use for each OTC health care
antiseptic product reflect the bacterial reductions that would be
achieved under conditions of such use. Thus, the effectiveness
requirements for determining whether an active ingredient is GRAE for
use in patient preinjection skin preparations should be consistent with
the actual use of that product. We agree that patient antiseptic skin
preparations used for preinjection involve a process lasting a much
shorter period of time, sometime seconds, compared to surgery, which
can last several hours, and that such preinjection use has a lower risk
of infection. For these reasons, we also agree that the effectiveness
requirements for preinjection should be different than the
effectiveness requirements for patient preoperative skin preparations.
We discuss these effectiveness requirements in more detail in section
V.D.2.
    We also note that, although we do not address labeling in this
final rule because at this time we have not found any active
ingredients to be GRAS/GRAE for use in patient antiseptic skin
preparations, we anticipate that labeling for these products will
include directions for use that will help providers determine the
proper use of preoperative and preinjection antiseptic products.
5. Food Handler Antiseptics
    (Comment 5) Several comments requested that FDA formally recognize
antiseptic hand washes and rubs used in the food industry as a distinct
food handler category subject to its own monograph. The comments also
requested that FDA confirm that food handler antiseptics can continue
to be marketed until FDA issues a food handler monograph.
    (Response 5) As stated in the 2016 Consumer Wash Final Rule (81 FR
61106 at 61109) and the 2015 Health Care Antiseptic PR (80 FR 25166 at
25168), we continue to classify the food handler antiseptic washes as a
separate and distinct monograph category. As explained in those
rulemakings, food handler antiseptic products are not part of these
rulemakings on the health care and consumer antiseptic monographs. We
continue to believe a separate category is warranted because of
additional issues raised by the public health consequences of foodborne
illness, differences in frequency and type of use, and contamination of
the hands by grease and other oils.

C. Comments on Eligibility of Active Ingredients and FDA Response

1. Benzethonium Chloride
    (Comment 6) In response to the 2015 Health Care Antiseptic PR, we
received a comment asserting that benzethonium chloride is eligible for
review under the monograph for use in health care personnel hand rubs
and surgical hand rubs and that benzethonium chloride be categorized as
a Category I ingredient for both indications. Information submitted in
the comment showed that methylbenzethonium chloride was present in
Bactine, a topical antiseptic for first aid and wound care before May
1972. The comment also asserted that:
     Methylbenzethonium chloride was the active ingredient in
the antiseptic, Bactine.
     Bactine with methylbenzethonium chloride was in use before
1972 as a leave-on antiseptic (not rinsed off).
     Methylbenzethonium chloride and benzethonium chloride are
equivalent.
     The conditions of use for benzethonium chloride in the
2015 Health Care Antiseptic PR are the same as for Bactine.
    (Response 6) In the 2015 Health Care Antiseptic PR (80 FR 25166 at
25171), we explained that 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. Conditions of use include active ingredient,
dosage form and dosage strength, route of administration, and the
specific OTC use or indication of the product. If the eligibility of a
product for OTC Drug Review is in question, FDA must have actual
product labeling or a facsimile of labeling that documents the
conditions of marketing the product before May 1972 (see Sec.
330.10(a)(2)). If benzethonium chloride was the active ingredient in a
drug before May 1972 for use as a health care personnel hand rub and/or
surgical hand rub, then it would be eligible for the OTC Drug Review
for those indications.
    We disagree with the comment's statement asserting that
methylbenzethonium chloride (the active ingredient in Bactine) is
essentially equivalent to benzethonium chloride based on their similar
structure and chemical function (both are quaternary ammonium chloride
antiseptic ingredients). Although these two ingredients are chemically
similar such that they could be grouped as quaternary ammonium
compounds, they are not equivalent molecules. Furthermore, although not
suggested by the comment, there is no evidence that methylbenzethonium
is a prodrug for benzethonium chloride, or requires

conversion or metabolism to benzethonium chloride for antiseptic
activity when applied to the skin.
    Moreover, although the comment provided data to demonstrate that
methylbenzethonium chloride was used in Bactine before May 1972, the
submitted label for Bactine contained indications that are not
equivalent to the indications for health care personnel hand rubs or
surgical hand rubs. The indications and directions on the Bactine label
(i.e., minor cuts, scratches, and abrasions; minor burns, sunburn;
itching skin irritations; shaving antiseptic; sickroom, nursery (hands,
thermometers, surgical instruments, sickroom articles); athlete's
foot--sore tired feet) do not support the use of benzethonium chloride
as an active ingredient used in a health care antiseptic hand rub by a
health care professional in the care of patients or by a surgeon before
surgery. The Directions for Use (indications) from the Bactine bottle
do not support the eligibility of methylbenzethonium chloride as an OTC
health care antiseptic hand rub or surgical hand rub. Lastly, although
the use of methylbenzethonium chloride to disinfect the hands is
suggested by the word ``hands'' in the directions for ``sickroom,
nursery (hands, thermometers, surgical instruments, sickroom articles)
use full strength Bactine,'' this reference to hands is imprecise and
no specific Directions for Use are provided.
    We also performed a literature search to investigate whether
benzethonium chloride was used as an active ingredient in an OTC health
care antiseptic leave-on product for the indication of a health care
personnel hand rub or surgical hand rub before May 1972. Our search did
not find evidence for the use of benzethonium chloride as a health care
personnel hand rub or surgical hand rub.
    In sum, we find that the data submitted in support of the
eligibility of benzethonium chloride as a monograph active ingredient
for use as a health care personnel hand rub and/or a surgical hand rub
do not demonstrate that benzethonium chloride is eligible for use for
these health care antiseptic indications. For these reasons, we find
that benzethonium chloride continues to be ineligible for evaluation
under the OTC Drug Review for use as a health care personnel hand rub
and surgical hand rub. Consequently, drug products containing
benzethonium chloride for use in health care personnel hand rubs and
surgical hand rubs will require approval under an NDA or ANDA prior to
marketing.
2. Chlorhexidine Gluconate
    (Comment 7) FDA received two comments asserting that chlorhexidine
gluconate should be eligible for inclusion in the OTC health care
antiseptic monograph. The comments also stated that more data are
needed to find chlorhexidine gluconate GRAS/GRAE for use as an OTC
health care antiseptic.
    (Response 7) Chlorhexidine gluconate was not included in the 1994
TFM because we had previously found chlorhexidine gluconate to be
ineligible for inclusion in the monograph for any health care
antiseptic use (80 FR 25166 at 25172, citing 59 FR 31402 at 31413). In
the 2015 Health Care Antiseptic PR, we explained that we had not
received any new information since the 1994 TFM that supported the
eligibility of chlorhexidine gluconate for inclusion in the monograph.
Consequently, we proposed not to change the categorization of
chlorhexidine gluconate based on the lack of documentation
demonstrating its eligibility under the OTC Drug Review for use as a
health care antiseptic (80 FR 25166 at 25172).
    The comments on chlorhexidine gluconate submitted in response to
the 2015 Health Care Antiseptic PR did not include any data or any new
information to support chlorhexidine gluconate's eligibility for
inclusion in the health care antiseptic monograph. Specifically, no
evidence was submitted for chlorhexidine gluconate to demonstrate that
chlorhexidine gluconate was an active ingredient in OTC health care
antiseptics in the United States before May 1972. Consequently, we find
that chlorhexidine gluconate continues to be ineligible for evaluation
under the OTC Drug Review for use as a health care antiseptic. Drug
products containing chlorhexidine gluconate for use in health care
antiseptics will require approval under an NDA or ANDA prior to
marketing. Because chlorhexidine gluconate continues to be ineligible
for consideration under the health care antiseptic monograph, it is
unnecessary to address the comments' statement that more safety and
effectiveness data are needed to find chlorhexidine gluconate GRAS/GRAE
for OTC health care antiseptic use.
    (Comment 8) In response to the 2015 Health Care Antiseptic PR, we
also received a comment expressing concerns regarding the bacterial
resistance of chlorhexidine gluconate. In addition, we received a
comment that suggested that chlorhexidine gluconate is superior to
povidone-iodine as a patient preoperative skin preparation.
    (Response 8) Because we find that chlorhexidine gluconate is
ineligible for consideration under the health care antiseptic monograph
and these comments do not have an impact on this finding, we do not
address these comments in this final rule.
3. Alcohol
    (Comment 9) In response to the 2015 Health Care Antiseptic PR, a
comment was submitted that argued that alcohol should be deemed
eligible for evaluation under the OTC Drug Review for use as a surgical
hand scrub. The comment asserted that FDA first made its distinction
between ``rubs'' and ``scrubs'' in the 2015 Health Care Antiseptic PR,
in which FDA proposed that alcohol was ineligible for inclusion in the
health care antiseptic monograph as a surgical hand scrub. The comment
stated that FDA based this conclusion on the fact that information for
rinse-off products was not submitted to the OTC Drug Review. But, the
comment claimed, manufacturers had no reason to submit such information
because FDA had found alcohol to be GRAS/GRAE for use in surgical hand
scrub products in the 1994 TFM, and manufacturers had no notice that
FDA was expecting such submissions. The comment argued that the
Agency's exclusion of alcohol from the 2015 Health Care Antiseptic PR
for use as a surgical hand scrub was arbitrary and capricious and in
violation of the Administrative Procedure Act (APA), 5 U.S.C.A.
sections 501 et seq.
    (Response 9) In the 2015 Health Care Antiseptic PR, we explained
that the 1994 TFM did not distinguish between products that we are now
calling ``antiseptic washes'' and products we are now calling
``antiseptic rubs.'' However, based on comments submitted in response
to the 1994 TFM, we tentatively determined that there should be a
distinction between antiseptic washes and antiseptic rubs, as well as a
distinction between consumer antiseptic and health care antiseptic
products. As evidenced by the comments received in response to the 1994
TFM, formulation practices and marketing intent of these products has
changed over time and products may not be eligible for conditions under
which they are currently marketed. We explained that washes are rinsed
off with water, and include health care personnel hand washes and
surgical hand scrubs, while rubs are sometimes referred to as ``leave-
on products'' and are not rinsed off after use, and include health care
personnel hand rubs,

surgical hand rubs, and patient preoperative skin preparations (80 FR
25166 at 25169). As a result of these distinctions, we proposed that
alcohol was ineligible for use as a health care personnel hand wash and
surgical hand scrub because the only health care antiseptic products
that contained alcohol for which evidence was submitted to the OTC Drug
Review for evaluation were products that were intended to be used
without water (i.e., rubs and skin preparations) (Id. at 25172).
    We disagree with the comment's assertions that manufacturers did
not have notice or an opportunity to submit information to the OTC Drug
Review on alcohol's eligibility for use as a surgical hand scrub.
First, we note that the 1994 TFM was a proposed rule, not a final rule;
we proposed, but had not yet found, alcohol to be GRAS/GRAE for use in
surgical hand scrub products. Moreover, in the 2015 Health Care
Antiseptic PR, our proposal that alcohol was ineligible for use as a
surgical hand scrub also was a preliminary determination based on the
lack of adequate evidence of eligibility for evaluation under the OTC
Drug Review. In the proposed rule, we invited parties to submit such
evidence of eligibility. We explained that if the documentation
demonstrated that an active ingredient met the OTC Drug Review
requirements, the active ingredient could be determined to be eligible
for evaluation for the specified use. Parties had 180 days to submit
comments on the proposed rule and 12 months to submit any new data or
information on the proposed rule, including evidence and documentation
on eligibility (80 FR 25166 at 25169). The comment submitted in
response to the 2015 Health Care Antiseptic PR on this issue did not
include any documentation or evidence to demonstrate that alcohol is
eligible for use as a surgical hand scrub under the OTC antiseptic
monograph, despite the opportunity to include such information. Also,
there was no additional data or information submitted to the record
thereafter to demonstrate alcohol's eligibility for evaluation under
the OTC Drug Review for use as a surgical hand scrub.
    For these reasons, we find that alcohol continues to be ineligible
for evaluation under the OTC Drug Review for use as a surgical hand
scrub. Consequently, drug products containing alcohol for use in
surgical hand scrubs will require approval under an NDA or ANDA prior
to marketing.
    We also note that where these active ingredients are ineligible for
evaluation under the OTC Drug Review, interested parties may have the
option to submit a time and extent application under Sec.  330.14 (21
CFR 330.14) of FDA's regulations to request that the Agency amend the
health care antiseptic monograph to include these active ingredients
for use in health care antiseptics for the specified indications.

D. Comments on Effectiveness and FDA Response

1. Clinical Simulation Studies
    (Comment 10) One comment stated that FDA should require the same
clinical studies that were required to show a benefit of OTC consumer
antiseptic washes over and above washing with non-antibacterial soap
for OTC antiseptics used in the health care setting. The comment
asserted that there are numerous safety concerns with the use of these
active ingredients and given these concerns and health care workers'
extensive exposure to these ingredients in their workplaces on a daily
basis, the Agency should find that there is a benefit over and above
washing with plain soap and water in order to make a GRAE determination
for these active ingredients. The comment stated that if FDA relies on
bacterial reduction as a proxy for effectiveness in the health care
setting, it must require that that reduction be compared against plain
soap and water, especially given that workers in the health care
setting likely wash their hands more frequently than the general
public, and thus, are exposed to higher levels of these ingredients.
    (Response 10) As we explained in the 2015 Health Care Antiseptic PR
(80 FR 25166 at 25175 to 25176), study design limitations and ethical
concerns prevent the use of clinical outcome studies to demonstrate the
effectiveness of active ingredients used in health care antiseptic
products. Participants at the March 2005 NDAC meeting acknowledged the
difficulty in designing clinical trials to demonstrate the impact of
health care antiseptics on rates of infection where numerous factors
contribute to hospital-acquired infections, and therefore, would need
to be controlled for in the design of these types of studies.
Participants at the March 2005 NDAC meeting recommended that
manufacturers perform an array of trials to look simultaneously at the
effect on the surrogate endpoint and the clinical endpoint to try to
establish a link between the surrogate and clinical endpoints, but
provided no guidance on possible study designs. At the time,
participants at the March 2005 NDAC meeting agreed that there were
currently no clinical trials presented that showed a definitive
clinical benefit for a health care antiseptic. However, recently, using
an active comparator, Tuuli et al. demonstrated fewer infections
following caesarean section with use of an approved patient
preoperative health care antiseptic (Ref. 6). Otherwise, we have seen
very few examples of well-controlled studies of this type to date.
    Participants at the March 2005 NDAC meeting also believed it would
be unethical to perform a hospital trial using a vehicle control
instead of an antiseptic given the concerns with performing placebo-
controlled studies on patients (Ref. 3). The inclusion of such control
arms in a clinical outcome study conducted in a hospital setting could
pose an unacceptable health risk to study subjects (hospitalized
patients and health care providers). In such studies, a vehicle or
negative control would be a product with no antimicrobial activity. The
use of vehicle or saline (a negative control) in a hospital setting (a
setting with an already elevated risk of infections) could increase the
risk of infection for both health care providers and their patients.
For these reasons, we continue to find that the use of clinical
simulation studies relying on surrogate endpoints to evaluate the
effectiveness of health care antiseptics is the best means available of
assessing the effectiveness of health care antiseptic products.
    (Comment 11) Given the ethical concerns with performing clinical
trials in a health care setting, one comment urged FDA to evaluate
natural experiments that have already occurred (e.g., hospital systems
that switched away from chemical antiseptics in hand washes) when
making a final monograph decision. The comment also stated that, while
the clinical simulation studies provide useful information about one
possible route through which bacterial illnesses are passed in a health
care setting, as currently designed these studies do not study the
complex microflora of the hospital environment, which is home to a wide
range of bacterial populations. The comment said that the bactericidal
effectiveness of the active ingredients is only partially achieved with
the in vitro testing. The comment explained that, in addition to the
MIC and time-kill testing, the in vitro tests for health care
antiseptics could mirror the ``worst-case'' real-world assumptions.
Clinical isolates that closely represent worst-case hospital or health
care microbial populations (e.g., large numbers of multi-drug resistant
bacterial strains) could be highly useful in determining

the effectiveness of an active ingredient under real-world conditions.
The comment stated that worst-case assumptions could include patient-
derived isolates from cases involving isolation due to multi-drug
resistance or isolates from frequently contaminated surfaces within a
hospital or health care setting (e.g., door knobs, soap dispensers);
and that this type of testing could be expanded into ``clinical
simulation'' studies by measuring log reduction of bacterial counts on
hands contaminated under actual health care conditions.
    (Response 11) We believe that applying health care-associated high
risk microbial pathogens (e.g., methicillin-resistant Staphylococcus
aureus) during clinical simulation studies raises the ethical and study
design issues we have discussed in this rulemaking. Currently, no
historical data have been submitted to the docket that address or
evaluate the effectiveness of health care antiseptic active ingredients
in health care settings. Also, we are not aware of any health care
personnel hand wash antiseptic that has been replaced with the use of
plain soap and water in the hospital setting, and no such data have
been submitted to the docket. Moreover, as explained in this
rulemaking, participants at the March 2005 NDAC meeting believed that
it would be unethical to perform hospital trial studies using a vehicle
control, such as plain soap and water, instead of an antiseptic.
    In addition, the standard infection control guidance broadly
implemented by CDC (Refs. 7 and 8), which involves measures such as
gloving, hand hygiene, patient-to-patient contact, and waste disposal,
makes it difficult to design an adequate clinical study (Ref. 9).
    Moreover, the in vitro testing required for proof of effectiveness
against microorganisms (80 FR 25166 at 25177 to 25178), is already
intended to characterize the activity (broad spectrum) of the
antimicrobial ingredient. The American Type Culture Collection (ATCC)
strains we reference in the 2015 Health Care Antiseptic PR for the in
vitro testing are chosen to represent a broad spectrum of bacteria that
present a challenge to antisepsis and are the principal bacterial
pathogens encountered in hospital settings. The clinical simulation
studies described in the 2015 Health Care Antiseptic PR are based on
the premise that bacterial reductions achieved using tests that
simulate conditions of actual use for each OTC health care antiseptic
product category reflect the bacterial reductions that would be
achieved under such conditions of use.

2. Log Reduction Testing Criteria

    (Comment 12) Multiple comments were submitted to the 2015 Health
Care Antiseptic docket on the in vivo testing criteria that use
bacterial log reductions for determining the effectiveness of active
ingredients used in health care antiseptic products. One comment stated
that single application testing and increased log reduction for health
care personnel hand rubs is not supported by scientific evidence and
that current gaps exist within the peer-reviewed literature. The
comment recommended that the Agency not change the testing requirements
for the health care personnel hand rub products because alcohol-based
hand rubs are used millions of times a day across the United States in
all health care facilities. The comment also asserted that the
recommended changes to the testing requirements by FDA could result in
the unavailability of hand hygiene products to the clinicians who
utilize them daily to prevent the transmission of health care
associated infections to patients. One comment also asserted that FDA
should retain the effectiveness criteria proposed for surgical hand
scrubs identified in the 1994 TFM for single applications only.
    Several comments also asserted that FDA should retain the
effectiveness criteria proposed in the 1994 TFM for health care
personnel hand wash and rub products as 2 log10 after a
single application. The comments argued that the proposed 2.5
log10 reduction with a 70 percent success criterion for
health care personnel hand wash products would be unattainable even by
current FDA-approved products. In addition, several comments suggested
that FDA adopt effectiveness criteria for in vivo effectiveness testing
of active ingredients in surgical hand rubs and scrubs of a 1
log10 reduction within one minute after the first
application procedure with no return to baseline within 6 hours.
    Several comments also asserted that it is inappropriate to propose
a 30-second contact time for patient preoperative skin preparations.
The comments argued that most active ingredients for use in patient
preoperative skin preparations would be unable to make the log
reduction effectiveness criteria at 30 seconds. The comments asserted
that, although it may be possible for some patient preoperative skin
preparation products to make the log reduction effectiveness criterion
and that it may be possible for some patient preoperative skin
preparation products to make the 70 percent success rate for abdomen,
no products can make the 70 percent success rate for the groin area at
30 seconds. One comment agreed with the 30-second time point, but
argued that sampling should include a time point after the drying time
is completed according to the directions. The comment stated that, in
the proposed amendment to the 1994 TFM, it is unclear whether the
antiseptic would be tested 30 seconds after application and while still
wet, potentially resulting in efficacy compromise. The comment asserted
that FDA should allow the product to fully dry before collecting 30-
second time point efficacy testing, especially with topical skin
antiseptics, because it is important that the skin be fully dry to
achieve maximum efficacy and also to minimize potential skin irritation
associated with use. Similarly, another comment asserted that, when
referring to time points after product application for patient
preoperative skin preparation, it should be explicitly stated that
``after product application'' means ``product application plus required
dry time.'' Several comments also stated that the proposed 10-minute
application period identified in the 1994 TFM is more representative of
current clinical application practices.
    (Response 12) As described in the 2015 Health Care Antiseptic PR,
we proposed revisions to the log reduction criteria for health care
personnel hand washes and rubs, and for surgical hand scrubs and rubs
based on the recommendations of the March 2005 NDAC meeting and
comments to the 1994 TFM that argued that the demonstration of a
cumulative antiseptic effect for these products is unnecessary (80 FR
25166 at 25178). 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 health care personnel hand washes and
rubs and surgical hand scrubs and rubs are used. Given that we were no
longer requiring a cumulative antiseptic effect, the log reduction
criteria were revised to reflect this single product application and
fall between the log reductions previously proposed for the first and
last application. Accordingly, we continue to find that the log
reduction criteria for these products should be applied to a single
application of the product rather than to multiple applications of the
product.
    Moreover, in the 2015 Health Care Antiseptic PR, we also proposed
that patient antiseptic skin preparations (i.e., patient preoperative
and preinjection skin preparations) be able to

demonstrate effectiveness at 30 seconds because we believed that
injections and some incisions are made as soon as 30 seconds after skin
preparation (80 FR 25166 at 25178). In vivo studies are based on the
premise that bacterial reductions achieved using tests that simulate
conditions of actual use for each health care antiseptic category
reflect the bacterial reductions that would be achieved under
conditions of such use. Accordingly, we find that the effectiveness
criteria for patient antiseptic skin preparations (i.e., patient
preoperative and preinjection skin preparations) should continue to
include the 30-second sampling time point. Also, we find that the 10-
minute sampling time point proposed in the 1994 TFM should also be
included in the effectiveness criteria as a time point option for
patient preoperative skin preparations. These products should be tested
at the 30-second or 10-minute sampling time point after drying,
according to the labeled directions for use. For patient preinjection
skin preparations, however, the 10-minute sampling time point should
not be a time point option. Patient preinjection skin preparations
should be tested at the 30-second time point only.
    Based on comments submitted on the 2015 Health Care Antiseptic PR
and the Agency's further evaluation of additional data, we have updated
the underlying statistical analysis related to the log reduction
criteria for classifying health care antiseptic active ingredients as
GRAE (Refs. 10, 11, 12, 13, 14, and 15).
    In the 1994 TFM, FDA recommended that the general effectiveness of
antiseptics be assessed in a number of ways, including conducting
clinical simulation studies with the surrogate endpoint of the number
of bacteria removed from the skin. In the 2015 Health Care Antiseptic
PR, FDA made revisions to the effectiveness criteria set forth 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 health care antiseptic 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; (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 (80 FR 25166 at 25178 to 25179). 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 and 2015 Health Care Antiseptic PR, we
find that bacterial log reduction studies should continue to be used to
demonstrate that an active ingredient is effective for use in a health
care antiseptic product. Also consistent with the 2015 Health Care
Antiseptic PR, subjects should be randomized to a three-arm study:
Test, active control, and negative control. However, based on comments
submitted on the 2015 Health Care Antiseptic PR and the Agency's
further evaluation of additional data, we are updating the statistical
analysis related to the log reduction criteria for classifying health
care antiseptic active ingredients as GRAE. Also, as we explain in
section V.B.4, we include separate effectiveness criteria for patient
preinjection skin preparations to more accurately reflect the actual
use of these products. We also clarify, for patient preoperative skin
preparations and patient preinjection skin preparations, that the
sampling time point commences after the applied product dries.
    The updated analysis is designed to assess whether the average
treatment effects (ATE) across subjects meet indication-specific
conditions of superiority and non-inferiority, rather than whether the
percentage of subjects who meet an indication-specific threshold
significantly exceeds 70 percent. More specifically, the updated
analysis estimates the ATE 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). 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 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 deferred 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 health care antiseptics should include the
following:
     The test product should be non-inferior to an FDA-approved
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. Non-inferiority to
active control should be met at the following area and times for the
respective health care antiseptic indications:
    [cir] Patient preoperative skin preparation:

[ssquf] Per square centimeter on abdominal site within 30 seconds after
drying, or within 10 minutes after drying
[ssquf] Per square centimeter on groin site within 30 seconds after
drying, or within 10 minutes after drying
[cir] Patient preinjection skin preparation: Per square centimeter on a
dry site (i.e., forearm, abdomen, or back) within 30 seconds after
drying
[cir] Health care personnel hand wash: On each hand within 5 minutes
after a single wash
[cir] Health care personnel hand rub: On each hand within 5 minutes
after a single rub.
[cir] Surgical hand scrub: On each hand within 5 minutes after a single
scrub
[cir] Surgical hand rub: On each hand within 5 minutes after a single
rub

     The test product should be superior to the vehicle control
by an indication-specific margin. That is, we expect the lower bound of
the 95 percent confidence interval of the ATE of the test product
compared to the vehicle control to be greater than the indication-
specific margin. In cases where the vehicle cannot be used as a
negative

control, nonantimicrobial soap or saline solution can be used. Based on
our evaluation of the existing data, the following indication-specific
superiority margin should be met by the deferred ingredients for the
respective health care antiseptic indications:

[cir] Superiority margin of 1.2 log10 for patient
preoperative skin preparation
[ssquf] per square centimeter on abdominal site within 30 seconds after
drying, or within 10 minutes after drying
[ssquf] per square centimeter on groin site within 30 seconds after
drying, or within 10 minutes after drying
[cir] Superiority margin of 1.2 log10 for patient
preinjection skin preparation per square centimeter on a dry site
(i.e., forearm, abdomen, or back) within 30 seconds after drying
[cir] Superiority margin of 1.2 log10 for health care
personnel hand wash on each hand within 5 minutes after a single wash
[cir] Superiority margin of 1.5 log10 for health care
personnel hand rub on each hand within 5 minutes after a single rub
[cir] Superiority margin of 0.5 log10 for surgical hand
scrub on each hand within 5 minutes after a single scrub
[cir] Superiority margin of 1.5 log10 for surgical hand rub
on each hand within 5 minutes after a single rub

    As discussed in more detail in section V.D.4, we believe that
persistence of antimicrobial effect is an important attribute for
health care antiseptic products, and in particular for patient
preoperative skin preparations, surgical hand scrubs, and surgical hand
rubs. To show persistence of effect for these health care antiseptic
indications, the 6 hours post-treatment measurement should be lower
than or equal to the baseline measurement for 100 percent of the
subjects in each indication and body area tested.
    Moreover, for the deferred ingredients, a minimum sample size of
100 subjects per treatment arm should be included for each indication.
This sample size will ensure that ATE will be estimated precisely for
the deferred ingredients and can be used for future reference in final
product monographs. Exact sample size can be based on the margins for
non-inferiority and superiority as well as an assessment of
variability. In addition, two adequate and well-controlled clinical
simulation pivotal studies should be conducted for each indication at
two separate independent laboratory facilities by independent principal
investigators.
3. Baseline Bacterial Count
    (Comment 13) Several comments asserted that the Agency does not
specify a minimum baseline bacterial count for subject eligibility in
the clinical simulation studies and that the 1994 TFM is vague with
regard to baseline values. The 1994 TFM states only that sites are to
possess bacterial populations large enough to allow demonstrations of
bacterial reduction of up to 2 log10 per square centimeter
on dry skin sites and 3 log10 per square centimeter on moist
sites (59 FR 31402 at 31450). One comment urged FDA to use baseline
values for patient preoperative skin preparations that follow the
American Society for Testing and Materials (ASTM) \3\ method E1173,
which is more specific and states that the bacterial baseline
population should be at least 3 log10 per square centimeter
on moist skin sites and at least 2 log10 greater than the
detection limit on dry skin sites. Several comments also stated that it
was challenging to find subjects who have resident bacterial counts
high enough to be eligible for these studies.
---------------------------------------------------------------------------

    \3\ General information about ASTM International can be found at
https://www.astm.org/.
---------------------------------------------------------------------------

    (Response 13) We do not specify a minimum baseline bacterial count
for subject eligibility in the clinical simulation studies; however,
the test sites should possess bacterial populations large enough to
meet the updated statistical criteria as explained in section III.D.2.
We do not specify a minimum baseline bacterial count because, as
explained in section III.D.2, the ATE is used to demonstrate
effectiveness. Rather than using only a change from baseline, each
criterion (groin site and abdomen site) uses the ATE, an estimated
difference of the effect of two treatments correcting for baseline
count. Manufacturers are encouraged to select subjects with baseline
counts significantly higher than the expected log reductions achieved
during the testing (i.e., high enough to allow for a positive residual
of bacterial burden after the use of the active control and the test
product). This selection will ensure that there is a high enough
bacterial count at baseline to assess the full effectiveness of both
the active control and the product under evaluation. Likewise, a
bacterial burden so low that it is depleted readily both by the vehicle
(or negative control) and by the test product, will not allow for an
assessment of the effectiveness of that test product because the
outcome would equally be zero and it will not be possible to measure
the difference in log reduction between the test product and negative
control. The number of viable microorganisms recovered from the skin of
each subject at baseline should be provided in the final study report.
In addition, given the updated statistical analysis criteria outlined
in section V.D.2, it is unnecessary to apply the baseline values for
patient preoperative skin preparations that follow the ASTM E1173
method.
    Moreover, if manufacturers find it challenging to recruit subjects
who have resident bacterial counts high enough to be eligible for these
studies, we recommend the use of the back as an alternate dry test
site, rather than using the arm. We do not recommend the use of an
occlusive dressing (sterile gauze). Covering the test sites has the
potential to change the make-up of the microbial population. Therefore,
the use of occlusion may not provide an accurate assessment of how
effective the product will be under actual use conditions.
4. Persistence
    (Comment 14) One comment stated that current infection control
procedures make persistence of antimicrobial activity for surgical hand
scrub and patient preoperative skin preparations irrelevant. The
comment asserted that persistence of effect may, in fact, be a negative
attribute for these products because it may cause irritation. The
comment suggested that the Agency place more emphasis on the mildness
of these products rather than the persistence of these products.
Another comment agreed with the Agency's requirement that patient
preoperative skin preparations and surgical scrubs have a persistent
antimicrobial effect. Another comment contended that the Agency's
statement about the need for persistence of effect for patient
preoperative hand scrubs lacks substantiating data. Another comment
stated that the concept of persistence of antimicrobial activity is not
consistent for surgical scrub and patient preoperative skin
preparations, nor is it consistent with clinical practice. The comment
asserted that the testing requirements for a patient preoperative skin
preparation limit the definition of persistence to 6 hours of sustained
activity after each product use. The comment recommended that
persistence for surgical hand scrub products be defined as sustained
activity of the antimicrobial formulation for a period of 6 hours after
product use. Another comment asserted that persistence should not be
required for any of the health care indications.
    (Response 14) In the 1994 TFM, we described the importance of
persistence as a characteristic of antiseptic drug

products. We agreed with the Advisory Review Panel on OTC Miscellaneous
External Drug Products' finding that persistence, defined as prolonged
activity, is a valuable attribute that assures antimicrobial activity
during the interval between washings and is important for a safe and
effective health care personnel hand wash. We agreed that a property
such as persistence, which acts to prevent the growth or establishment
of transient microorganisms as part of the normal baseline or resident
flora, would be an added benefit (59 FR 31402 at 31407). Accordingly,
we proposed to include the persistence requirement in the definitions
of patient preoperative skin preparations and surgical hand scrubs
because we believe that persistence of antimicrobial effect would
suppress the growth of residual skin flora not removed by preoperative
prepping as well as transient microorganisms inadvertently added to the
operative field during the course of surgery and reduce the risk of
surgical wound infection. Specifically, we proposed to define patient
preoperative skin preparation to be a fast acting, broad spectrum, and
persistent antiseptic containing preparations that significantly reduce
the number of micro-organisms on intact skin, and we proposed to define
surgical hand scrub drug products to be an antiseptic containing
preparation that significantly reduces the number of microorganisms on
intact skin; it is broad spectrum, fast acting, and persistent (59 FR
31402 at 31442). In addition, although we do not require persistence
for health care personnel hand washes, we did propose to retain the
words ``if possible, persistent'' in the definition of health care
personnel hand wash (59 FR 31402 at 31442).
    FDA continues to believe that persistence of antimicrobial effect
is an important attribute because it can suppress the growth of
residual skin flora, as well as transient microorganisms not removed by
preoperative prepping or hand scrubbing. FDA is also aware that the
donning of surgical gloves may produce a rapid increase in microbial
count on the hands (Refs. 16, 17, and 18), even after use of a surgical
hand antiseptic product, which is another reason why persistence of
effect is a critical characteristic for antiseptic products.
Accordingly, we find that persistence is a requirement for surgical
hand scrubs, surgical hand rubs, and patient preoperative skin
preparations. We find that these antimicrobial products must be fast-
acting and consist of broad spectrum, persistent antiseptic-containing
preparations that significantly reduce the number of microorganisms on
intact skin. As discussed in section V.D.2 of this final rule, to show
the persistence of effect for these health care antiseptic indications,
the 6 hours post-treatment measurement should be lower than or equal to
the baseline measurement for 100 percent of subjects for each
indication and body area tested.
5. Controls
    (Comment 15) Several comments objected to the use of controls
because we do not specify what positive control material to use in the
effectiveness studies. One comment contended that, because the Agency
does not specify the control product, the test results will differ
depending on the effectiveness of the positive control. Another comment
recommended that we convene an expert panel to develop standard
positive controls. They cite the trend, on a worldwide basis, to
identify and adopt standardized testing procedures. They believe it
would be far better for the international harmonization effort if a
standard chemical, rather than a specific product or commercial
formulation, was used as the control. For these reasons, the comment
recommended that the positive control should be a standard chemical
that can be produced on a global basis and will perform consistently
and reproducibly.
    Other comments requested that we clarify how to interpret the
results of the positive control. One comment asked if our standard is
meeting the required log reduction, superiority to the positive
control, or both. Another comment pointed out that the Agency does not
define the criterion for an acceptable outcome for the positive
control. For instance, the comment states that it is unclear if an 80
percent success rate in the positive control for a surgical hand scrub
would be acceptable and if so, whether the new treatment could be 20
percent less successful than the positive control and still be
equivalent. For health care personnel hand washes, they assert that it
is not clear if the control must meet the requirements of 2 and 3
log10 reduction at the lower 95 percent confidence interval
limit or an average. The comment requested that FDA specify criteria
for validity of the study in terms of the positive control and criteria
for concluding that a test material is effective in terms of
equivalence to the positive control. One comment noted that the
Agency's proposed patient preoperative skin preparation treatment
application procedure does not include any reference to the active
control sites.
    Several comments agreed that the Agency's proposed changes to the
in vivo efficacy testing will reflect more accurately the real world
use of topical antiseptic drug products. The comments requested that
the Agency provide a validated ``gold standard'' for use as an active
control. One comment stated that it is appropriate that GRAS/GRAE
active ingredients would serve as the active control for any
effectiveness studies required for final formulations. For example, the
comment explained that alcohol at the concentration and application
instructions evaluated in the pivotal studies to help establish GRAS/
GRAE status would become the active control for effectiveness studies
involving alcohol-based final formulations. This would be more
appropriate than using an FDA-approved product for the active control,
particularly for alcohol-based hand sanitizer products where the only
FDA-approved drug is a dual-active product.
    (Response 15) We do not define a specific positive control material
to use in the effectiveness studies in this final rule, but we do
recommend the use of an appropriate FDA-approved NDA antiseptic as the
positive control (i.e., active control) when conducting the
effectiveness testing of health care antiseptic active ingredients. We
recognize that many countries have adopted standard chemicals for their
active controls. However, we still believe that we cannot define a
specific active control product for the following reasons:
     We do not have sufficient data to choose a specific
universal active control product that will be appropriate for all test
formulations or active ingredients.
     Changes to the formulation or manufacturing of the chosen
active control product might affect its activity in future studies.
Consequently, products tested against the modified active control might
not be held to the same standards as products tested previously.
    Although we do not identify a specific control product, we do
identify test criteria for the active control. As described in section
V.D.2, we recommend the use of non-inferiority of the test product to
an FDA-approved active control by a margin of 0.5 (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 show superiority of the test

drug product, but to show that the test drug product is not inferior.
    In addition, we recommend the use of an active control product of
the same type as the test product. For example, if the test product is
a leave-on surgical hand antiseptic, then an FDA-approved leave-on
surgical hand antiseptic should be used as the active control rather
than a rinse-off surgical hand antiseptic. We believe it is more
appropriate to compare similar types of products.
    (Comment 16) One comment stated that a vehicle typically refers to
the product formulated without the active ingredient. The comment
recommended that the term ``vehicle'' be replaced with the term
``negative control.'' Another comment requested that FDA clarify
whether testing of the vehicle is required.
    (Response 16) We recognize that the term ``negative control'' may
be broader than the term ``vehicle,'' and we agree that the term
``vehicle'' should be replaced with the term ``negative control'' where
applicable. As discussed in section V.D.2, we recommend that the
effectiveness testing study design for health care antiseptic active
ingredients include a negative control arm, which is used as a
comparator for the test product. The appropriate negative control to be
used in the studies is the test product's vehicle, which we interpret
to be the same product being tested, without the active ingredient
included, and therefore, best represents the independent contribution
of the antiseptic active ingredient. Because the same directions for
use will apply to the negative control and the test product, this
should account for any potential mechanical removal of microorganisms,
which occurs during the rubbing, scrubbing, wiping, or rinsing process,
independent of the active ingredient effect. If there is a scientific
reason why testing a product using its vehicle as a negative control is
not feasible, discussions can be had with FDA to determine whether the
use of an alternative negative control, such as a saline solution or
nonantimicrobial soap (for health care personnel and surgical hand
antiseptics), may be acceptable.
    We note that the testing described in this document pertains to
single active ingredients. Manufacturers should contact us if, in the
future, they would like to develop a fixed-combination health care
antiseptic drug product.
6. In Vitro Testing
    (Comment 17) One comment outlined the Agency's proposed
requirements listed in the 2015 Health Care Antiseptic PR (80 FR 25166
at 25177 to 25178) for an evaluation of the spectrum and kinetics of
antimicrobial activity of a health care antiseptic as including the
following:
     A determination of the in vitro spectrum of antimicrobial
activity against recently isolated normal flora and cutaneous
pathogens;
     Minimum inhibitory concentration (MIC) or minimum
bactericidal concentration (MBC) testing of 25 representative clinical
isolates and 25 reference strains of each of the microorganisms listed
in the 1994 TFM; and
     Time-kill testing of each of the microorganisms listed in
the 1994 TFM to assess how rapidly the antiseptic active ingredient
produces its effect. The dilutions and time points tested should be
relevant to the actual use pattern of the final product.

The comment requested that we confirm that the first bullet is meant to
describe what will be learned from the studies outlined in the last two
bullets because they do not recognize the first bullet as an actual
study. The comment also asked for confirmation that the emergence of
resistance testing is no longer a requirement.
    Another comment stated that the Agency has proposed in vitro
testing of 1,150 microorganisms (25 clinical isolates and 25 reference
isolates for 23 microorganisms). The comment argued that the Agency's
suggestion that previous tests of the same or similar strains are no
longer valid is arbitrary and that the requirement for new repeated
tests is unduly burdensome. The comment asserted that the proposed
number of clinical and reference isolates far exceeds the number
required for FDA-approved hand hygiene products, which have
successfully completed the review process. The comment recommended that
organisms of current clinical value as well as recent clinical isolates
be utilized to better assess the in vitro efficacy of these active
ingredients. Another comment similarly asserted that the microorganisms
identified by FDA for antimicrobial activity testing do not include
pathogens that are relevant to current health care settings; the
comment argued that the list should include Methicillin-resistant
Staphylococcus aureus, Methicillin-resistant Staphylococcus
epidermidis, Vancomycin-resistant Enterococcus; Enterococcus faecalis
and Enterococcus faecium). Another comment proposed that FDA should
consider adequate justifications for testing fewer than the identified
strains for organisms where 25 clinical isolates and/or 25 standard
strains are not available for screening active ingredients.
    (Response 17) We agree that the determination of the in vitro
spectrum of antimicrobial activity against recently isolated normal
flora and cutaneous pathogens is meant to describe what will be learned
from the MIC and/or MBC and time-kill studies and is not intended to be
a separate study. With regards to testing for the emergence of
resistance, we are requiring resistance testing for three of the six
deferred active ingredients--benzalkonium chloride, benzethonium
chloride, and chloroxylenol (Refs. 10, 11, 12, 13, 14, and 15).
However, we are not requiring resistance testing for the other three
deferred active ingredients--ethyl alcohol, isopropyl alcohol, and
povidone-iodine (see section V.D.2).
    In addition, we disagree that we are suggesting that previous tests
of the same or similar strains are no longer valid. In the 2015 Health
Care Antiseptic PR, we proposed the option of assessing the MBC as an
alternative to testing the MIC. We also reiterated our proposal that
the evaluation of the spectrum and kinetics of antimicrobial activity
of health care antiseptic active ingredients should include MIC (or
MBC) testing of 25 representative clinical isolates and 25 reference
(e.g., ATCC) strains of each of the microorganisms listed in the 1994
TFM, in addition to the other proposed requirements. In the 2015 Health
Care Antiseptic PR, we noted that, despite the fact that the in vitro
data submitted to support the effectiveness of antiseptic active
ingredients were far less extensive than proposed in the 1994 TFM,
manufacturers may have data from their own product development programs
which they have not submitted to the docket and/or that published data
may have become available that would satisfy some or all of the data
requirements (80 FR 25166 at 25178).
    As we explained in the 2015 Health Care Antiseptic PR, we agree
that the in vitro testing proposed in the 1994 TFM is not necessary for
testing every final formulation of an antiseptic product that contains
a GRAE ingredient (80 FR 25166 at 25177). However, we continue to
believe that a GRAE determination for health care antiseptic active
ingredients should be supported by adequate in vitro characterization
of the antimicrobial activity of the ingredient. We note that, for the
six deferred active ingredients, the Agency is reviewing proposed
protocols for the safety and effectiveness studies, including the list
of organisms for the time-kill testing and MIC/MBC testing, which may
include additional resistant organisms that are relevant to current
health care settings.

7. American Society for Testing and Materials Standards
    (Comment 18) Several comments proposed that the Agency recognize
specific ASTM protocols as standardized test methods for demonstrating
that an active ingredient is GRAE for use in health care antiseptics
and demonstrating effectiveness for final product formulations. These
ASTM test methods include the ASTM E1174 ``Standard Test Method for the
Evaluation of the Effectiveness of Health Care Personnel Handwash
Formulations''; the ASTM E2755-10 ``Standard Test Method for
Determining the Bacteria-Eliminating Effectiveness of Hand Sanitizer
Formulations Using Hands of Adults''; the ASTM E1115-11 ``Standard Test
Method for Evaluation of Surgical Hand Scrub Formulations''; the ASTM
E1173-15 ``Standard Test Method for Evaluation of Preoperative,
Precatheterization, or Preinjection Skin Preparations''; the ASTM E1054
``Standard Test Methods for Evaluation of Inactivators of Antimicrobial
Agents''; the ASTM E2783 ``Standard Test Method for Assessment of
Antimicrobial Activity for Water Miscible Compounds Using a Time-Kill
Procedure''; and the Clinical and Laboratory Standards Institute M07-
A10 ``Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically.''
    (Response 18) For purposes of the six deferred active ingredients,
we have reviewed these test methods and believe they may be useful to
help establish GRAE status for the health care antiseptic products for
their respective indications. 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.
    Testing requirements for final formulation, however, are not
addressed in this final rule because none of the active ingredients
subject to this final rule have been found to be GRAE for use in health
care antiseptic products. The testing requirements for final
formulation of these products containing the six deferred active
ingredients will be addressed after a decision is made regarding the
monograph status of those ingredients.

E. Comments on Safety and FDA Response

1. Need for Additional Safety Data
    (Comment 19) One comment supported FDA's proposal to require
additional safety data for the health care antiseptic active
ingredients. The comment agreed that more testing is needed to support
a GRAS determination for these active ingredients. Other comments,
however, asserted that the safety testing proposed in the 2015 Health
Care Antiseptic PR for active ingredients used in health care
antiseptics is unnecessary and burdensome. The comments asserted that
FDA has not provided data to justify that additional safety data are
needed for these ingredients to make a GRAS determination and stated
that the extensive historical use of these products should serve as
proof of the products' safety and effectiveness.
    Another comment stated that FDA must document how the systemic
absorption levels of active ingredients from the use of health care
antiseptics differ from FDA's previous assessment of the safety of
these ingredients. The comment asserted that, given the lack of
information on FDA's current position on the specific details regarding
risk assessment, FDA should consider in vitro data and dose-
extrapolation data.
    Another comment suggested that long-term systemic exposure to
active ingredients used in health care antiseptics could be reduced if
the efficacy standards for these products were decreased because lower
dose products could be formulated.
    (Response 19) We continue to believe that the additional safety
data outlined in the 2015 Health Care Antiseptic PR are necessary to
support a GRAS classification for the health care antiseptic active
ingredients. As was explained in the 2015 Health Care Antiseptic PR,
several important scientific developments that affect the safety
evaluation of the health care antiseptic active ingredients have
occurred since FDA's 1994 evaluation. New data and information on the
health care antiseptic active ingredients raise concerns regarding
potential risks from systemic absorption and long-term exposure, as
well as development of bacterial resistance related to widespread
antiseptic use (80 FR 25166 at 25167). Data that meet current safety
standards are needed for FDA to conduct an adequate safety evaluation
to ensure that health care antiseptic active ingredients are GRAS.
Moreover, as previously explained in this document, the September 2014
NDAC meeting participants discussed FDA's proposed revisions to the
safety data requirements and agreed that these requirements were
appropriate to demonstrate that a health care antiseptic active
ingredient is GRAS. Participants at the September 2014 NDAC meeting
further concluded that these safety standards are reasonable and
considered them to be minimal safety standards for currently available,
as well as future healthcare antiseptic products (Ref. 19).
    Moreover, the long history of use of a drug product is not
sufficient to demonstrate the safety of the product. In the case of
antiseptic products, the Agency has requested safety data in both the
1994 TFM and the 2015 Health Care Antiseptic PR in order to finalize
the antiseptic rules. Relying solely on adverse event reporting cannot
fill data gaps regarding risks such as reproductive toxicity or
carcinogenicity. As an example, phenolphthalein was an OTC product with
a long history of use as a laxative, but when animal studies were
conducted, evidence of carcinogenicity was detected. The April 30,
1997, FDA Center for Drug Evaluation and Research (CDER)
Carcinogenicity Assessment Committee (CAC) meeting concluded that there
was supportive evidence indicating that phenolphthalein may be
carcinogenic through a genotoxic mechanism. FDA concluded