[Federal Register Volume 82, Number 243 (Wednesday, December 20, 2017)]
[Rules and Regulations]
[Pages 60474-60503]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-27317]



[[Page 60473]]

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

[[Page 60474]]


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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

[[Page 60475]]

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.

[[Page 60476]]

[GRAPHIC] [TIFF OMITTED] TR20DE17.000


                                       Executive Order 13771 Summary Table
                           [In $ millions 2016 dollars, over an infinite time horizon]
----------------------------------------------------------------------------------------------------------------
                                                                                    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

------------------------------------------------------------------------
         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.

[[Page 60477]]

 
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.
------------------------------------------------------------------------

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

[[Page 60478]]

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\
---------------------------------------------------------------------------

    \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.''
---------------------------------------------------------------------------

    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\
------------------------------------------------------------------------
     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.

[[Page 60479]]

 
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.

[[Page 60480]]



                                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

[[Page 60481]]

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,

[[Page 60482]]

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

[[Page 60483]]

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

[[Page 60484]]

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,

[[Page 60485]]

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

[[Page 60486]]

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

[[Page 60487]]

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

[[Page 60488]]

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

[[Page 60489]]

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

[[Page 60490]]

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.

[[Page 60491]]

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 
``phenolphthalein caused chromosome aberrations, cell transformation, 
and mutagenicity in mammalian cells. Because benign and malignant tumor 
formation occurs at multiple tissue sites in multiple species of 
experimental animals, phenolphthalein is reasonably anticipated to have 
human carcinogenic potential.'' This conclusion led to the removal of 
phenolphthalein from the market (64 FR 4535, 4538) (Ref. 20).
    Finally, in this context, the safety data required to make a final 
GRAS determination on active ingredients used in health care antiseptic 
products would remain the same even if FDA determined that the data 
requirements necessary to make a GRAE determination should be changed.
    (Comment 20) Several comments also stated that the additional 
testing requirements could cause disruptions of the availability of 
health care antiseptics for clinical use. One comment urged the Agency 
to fully consider the consequences of the additional testing 
requirements, especially at a time when hand hygiene is considered to 
be the cornerstone for preventing the spread of pathogenic organisms in 
health care settings.
    (Response 20) We agree that health care antiseptic products are an 
important component of infection control strategies in health care 
settings and remain the standard of care to prevent illness and the 
spread of infections (Refs. 7 and 8). As we emphasized in the 2015 
Health Care Antiseptic PR, our proposal for more safety and 
effectiveness data for health

[[Page 60492]]

care antiseptic active ingredients does not mean that we believe that 
health care antiseptic products containing these ingredients are 
ineffective or unsafe. However, data that meet current safety 
requirements are still needed to support a GRAS determination for these 
active ingredients used in health care antiseptic products.
    We do not believe that these additional testing requirements will 
disrupt the availability of health care antiseptics for clinical use. 
As explained in the 2015 Health Care Antiseptic PR, we provided a 
process for seeking an extension of time to submit the required safety 
and/or effectiveness data if needed (80 FR 25166 at 25169). As 
discussed in this document, we have deferred further rulemaking on six 
active ingredients used in OTC health care antiseptic products to allow 
for the development and submission of new safety and efficacy data. 
Although in this final rule we find that the 24 non-deferred active 
ingredients are not GRAS/GRAE for use in OTC health care antiseptic 
products, health care antiseptic drug products that have been approved 
under an NDA or that contain one or more of the six deferred active 
ingredients still continue to be available.
    Accordingly, we do not believe that the additional testing 
requirements will cause a disruption in the availability of OTC health 
care antiseptic products.
    (Comment 21) Another comment asserted that FDA's reasons for 
requesting additional safety data are flawed. The comment stated that 
FDA should analyze all existing hazard data and consider the extent of 
human or environmental exposure as part of the process for deciding the 
nature and extent of hazard data required to understand potential 
safety concerns. The comment asserted that data generation based on an 
understanding of human exposure prevents the irresponsible use of 
laboratory animals and waste of resources necessary to generate 
toxicology data that will not further inform potential safety 
decisions.
    The comment also contended that the safety data gaps cited by FDA 
for the ingredients in the 2015 Health Care Antiseptic PR (human 
pharmacokinetics, animal pharmacokinetics, carcinogenicity, 
reproductive toxicity, potential hormonal effects, and potential 
antimicrobial resistance) do not all have to be filled in order for FDA 
to make a GRAS determination. In support of its position, the comment 
cited FDA's presentation to the September 2014 NDAC meeting, and listed 
FDA's stated criteria associated with the GRAS standard, including: (1) 
A low incidence of adverse events when used as directed and in the 
context of warnings; (2) low potential for harm if abused under 
conditions of widespread availability; (3) significant human marketing 
experience; (4) and, adequate tests to show proof of safety, among 
other criteria. The comment stated that FDA is not taking into account 
the low incidence of adverse events associated with the use of 
antiseptic active ingredients and the overall acceptance of these 
products globally. The comment also mentioned that numerous scientific 
and regulatory bodies have performed exposure-driven risk assessments 
and have not required the types of human or animal data mentioned in 
the 2015 Health Care Antiseptic PR.
    (Response 21) FDA presented the safety paradigm for OTC health care 
antiseptics at the September 2014 NDAC meeting (Ref. 21) where the 
Agency sought NDAC's advice about the type and scope of safety data 
needed for OTC health care antiseptic products. In FDA's presentation 
to NDAC, we explained that when evaluating a proposed monograph active 
ingredient, FDA applies the following regulatory standards, which are 
cited in 21 CFR 330.10(a)(4)(i):
     Safety means a low incidence of adverse reactions or 
significant side effects under adequate directions for use and warnings 
against unsafe use, as well as low potential for harm which may result 
from abuse under conditions of widespread availability.
     Proof of safety shall consist of adequate tests by methods 
reasonably applicable to show the drug is safe under the prescribed, 
recommended, or suggested conditions of use. This proof shall include, 
but not be limited to, results of significant human experience during 
marketing.
     General recognition of safety shall ordinarily be based 
upon published studies, which may be corroborated by unpublished 
studies and other data.
    As FDA explained in its presentation, the proposed safety studies 
are necessary to provide data that are needed to support a GRAS 
determination for the health care antiseptic active ingredients. The 
NDAC unanimously agreed that the safety standards proposed by FDA are 
appropriate to support a GRAS determination for a health care 
antiseptic active ingredient. The NDAC also noted that the safety 
standards presented by FDA are reasonable minimal safety standards for 
the currently available antiseptics, as well as for products to be 
formulated in the future (Ref. 19) and are required to support a GRAS 
determination for these ingredients.
    In terms of animal testing, the September 2014 NDAC meeting 
addressed the issue of the appropriateness of conducting animal studies 
to obtain safety data for health care antiseptic products (Ref. 4). We 
understand that animal use in tests for the efficacy and safety of 
human and animal products has been and continues to be a concern, and 
FDA continues to support efforts to reduce animal testing, particularly 
where new alternative methods for safety evaluation have been validated 
and accepted by International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) regulatory 
authorities. To address this issue, we encourage manufacturers to 
consult with the Agency on the use of non-animal testing methods that 
may be suitable, adequate, validated, and feasible to fill important 
data gaps that cannot be filled with marketing experience alone. 
However, there are still many areas where non-animal testing has not 
been sufficiently developed as an alternative option and animal studies 
are still considered necessary to fill important safety gaps (Refs. 4 
and 19).
2. MUsT Requirements
    (Comment 22) One comment asserted that FDA should reconsider the 
need to conduct MUsTs to assess systemic exposures associated with 
extreme use applications. The comment stated that the clinical utility 
of this testing has not been firmly established and the methodology 
necessary to conduct this type of testing has yet to be clearly 
validated to establish its utility. The comment argued that these types 
of studies need significant further development and validation before 
considering them a reliable method for systemic absorption studies and 
further guidance from FDA is needed. The comment said that FDA should 
also consider the use of existing modeling methods as a means to assess 
potential systemic exposure to avoid unnecessary clinical testing of 
active ingredients where modeling is available in conjunction with 
animal data.
    (Response 22) The MUsT paradigm has been used in the evaluation of 
topical dermatological agents approved in the United States since the 
early 1990s. It represents over 20 years of interactions with multi-
national drug companies, during which time the study design has been 
refined into its current state. Moreover, the MUsT is a published 
methodology that has been

[[Page 60493]]

presented at both national and international meetings. In addition, 
with respect to the six deferred active ingredients, FDA has been 
reviewing the MUsT protocol designs submitted by the manufacturers and 
trade organizations that have requested deferrals.
    FDA also understands and recognizes the potential of 
pharmacokinetic (PK) and physiologically-based pharmacokinetic (PBPK) 
modeling. FDA has considered these options and concluded that the 
currently proposed alternatives, including in silico, in vitro, and 
PBPK modeling, are not adequately validated to be a substitute for the 
MUsT described in the 2015 Health Care Antiseptic PR. We also note 
that, going forward, in order to validate the PBPK or any other 
alternative modeling-based approach, one would need, as part of their 
validation, a direct performance comparison to a series of in vivo 
MUsTs as part of the process to demonstrate the comparability and 
reproducibility of the results between the tests. For these reasons, we 
find that results from a human PK MUsT are needed to support a GRAS 
determination for active ingredients used in health care antiseptic 
products.
    (Comment 23) Another comment disagreed with FDA's position that the 
lack of pharmacokinetic data prevents FDA from calculating a margin of 
exposure for the risk assessment. The comment asserted that, although 
the safety evaluation of drugs may rely on correlating findings from 
animal toxicity studies to humans based on kinetic information in both 
species, safety evaluations for antiseptic ingredients in health care 
products are not based on kinetic information under standard 
international practice. Instead, the comment argued, safety evaluations 
are based on conservative assumptions of exposure and potential 
differences between species, and kinetic information is only required 
when use of these conservative assumptions fails to provide a 
sufficient margin of exposure. The comment stated that using these 
conservative and internationally accepted approaches, other scientific 
bodies and regulatory authorities have been able to complete the risk 
assessment for these types of ingredients in formulations with much 
greater levels of human exposure than these health care antiseptic 
uses. The European Commission Scientific Committee on Consumer Safety 
Guidance for the Testing of Cosmetic Substances and Their Safety 
Evaluation (8th Revision) was cited as a justification for this 
concept. Based on this reasoning, the comment asserted that FDA should 
not require additional animal testing unless the following conditions 
are met:
     Use of conservative approaches to calculate the margin of 
exposure is inadequate.
     The margin of exposure justifies the need for more data, 
but it is not possible to generate the data by non-animal approaches, 
such as using physiologically-based pharmacokinetic modeling, or 
through animal alternative test methods.
     There is perceived need for all active ingredients to have 
the same type of information.
    (Response 23) Calculating the margin of exposure was one of the 
topics discussed at the September 2014 NDAC meeting (Refs. 4 and 19). 
At that time, the consensus reached was that these types of 
calculations are more informed when taking the results of the MUsT-
acquired data and using that information along with the pharmacology/
toxicology results in the calculation of the safety margin. We also 
note that the references the comments provided for the risk assessment 
strategies that are followed by other international agencies are for 
cosmetic ingredients rather than for drug products. Accordingly, the 
referenced guidance may be designed to address different concerns than 
those at issue here.
    (Comment 24) Another comment stated that FDA should reconsider the 
concept of the MUsT and its value in determining the safety of health 
care antiseptic products. The comment said that the 2015 Health Care 
Antiseptic PR would require a MUsT to characterize maximum systemic 
exposure following health care antiseptic product use during the course 
of a work day or shift in health care settings. The comment stated that 
measured levels determined by the MUsT would establish the maximum 
systemic dose for the active ingredient in the particular antimicrobial 
product type, and the representativeness of the measured systemic 
active concentration would be dependent upon a number of variables 
associated with this trial, including the number of applications made 
per day or shift, the appropriate usage of the product, the 
concentration of active ingredient in the tested product, the 
sensitivity of the analytical method applied, and the extent to which 
the experimental protocol matches or approximates the actual usage of 
the product in the health care setting. The comment asserted that the 
use of the same product in different health care settings (e.g., out-
patient clinics or offices vs. emergency rooms or operating rooms) can 
be expected to have different patterns of use.
    The comment also argued that limitations exist in the practical 
conduct of a MUsT that influence and dictate what may be achieved by a 
specific protocol. The comment stated that practical requirements, for 
instance, the time needed to collect biological samples, or even to 
perform washing or application of the product, will dictate how many 
washes or applications are possible in a given time period regardless 
of what may be deemed desirable or required to evaluate perceived or 
empirical usage. As a result, the comment argued, the MUsT conditions 
described in the 2015 Health Care Antiseptic PR will result in assays 
that are very large and complex, and there is very little precedent to 
consult in the published literature. The comment also argued that the 
practical aspects of conducting a MUsT dictate what can reasonably be 
performed in terms of number of product applications, number of 
subjects, study arms, and timing. The comment asserted that if the 
defined, or desired, maximal use is not achievable in a MUsT and the 
resulting data do not meet the needs of the safety and risk assessment 
process, it is reasonable to question the utility, and expense, of 
conducting the study at all.
    (Response 24) The MUsT intends to reflect the upper end of use 
expected in the real-world. Because the MUsT is designed to represent, 
as closely as possible, the maximal use of the health care antiseptic 
product under actual use conditions in the health care setting, the 
conduct of the trial itself should be feasible. The goal of the MUsT is 
to evaluate absorption under conditions of maximum use, so lower rates 
of application, different sites, and different frequency of application 
will be covered. As we also mentioned, with respect to the six deferred 
active ingredients, FDA is reviewing protocol designs for the 
respective deferred active ingredients.
    (Comment 25) Another comment stated that, while data on the level 
of active ingredient in systemic circulation is arguably important for 
risk and safety assessment, it is not clear what any observed levels 
from MUsT may mean in this context in regards to risk and safety 
assessment. The comment argued that FDA has provided little guidance on 
how the MUsT data are used and that FDA has provided no data to 
indicate that there are any safety issues associated with any of the 
six active ingredients identified in the comment (alcohol, isopropyl 
alcohol, benzalkonium chloride, benzethonium

[[Page 60494]]

chloride, povidone-iodine, and chloroxylenol). The comment also 
asserted that, while the MUsTs will provide information on active 
ingredient levels in systemic circulation, it fundamentally remains a 
pharmacokinetic study. As such, the comment argued, it is not apparent 
that results from a MUsT will provide data that could not be better 
determined by an alternative or otherwise validated and accepted 
approach.
    (Response 25) We disagree with the comment's assertion that the 
Agency has not provided any data to indicate that there are safety 
issues associated with the six active ingredients identified in the 
comment, which are the six active ingredients we have deferred from 
this rulemaking. Based on known available data, including data 
submitted by the interested parties, FDA identified and summarized 
safety concerns and safety data gaps for the health care active 
ingredients at the September 2014 NDAC meeting (Refs. 4 and 21) and in 
the 2015 Health Care antiseptic PR (80 FR 25166 at 25179 to 25195).
    Moreover, the MUsT approach was specifically discussed at the 
September 2014 NDAC meeting (Refs. 4, 19, and 21). Information on 
systemic exposure derived from the MUsTs is necessary to determine a 
safety margin for the active ingredients. A margin of safety is a 
calculation that takes the no observed adverse effect level (NOAEL) 
derived from animal data and estimates a maximum safe level of exposure 
for humans, the data for which would be derived from data generated in 
the MUsT. In its objection to the proposed MUsT requirements, the 
comment did not provide an alternative or other validated and accepted 
approach available to assess human systemic exposure to the active 
ingredients (Refs. 4 and 21).
    (Comment 26) Another comment stated that if MUsTs are to be 
executed, field studies of health care facility application frequency 
would be necessary to determine maximum rates as adequate data do not 
currently exist. The comment asserted that while these studies could 
take the form of a direct observational study, other avenues may also 
be considered, such as the use of automated hand hygiene monitoring 
data. The comment also stated that this data acquisition approach is 
not subject to behavioral modification interferences by the observer, 
or hospital department access restrictions, such as the intensive care 
and surgery units. The comment asserted that this technology has 
recently progressed substantially in its sophistication and data 
reliability.
    (Response 26) As was mentioned earlier, FDA is discussing the 
design and conduct of their MUsT program of studies for the six 
deferred active ingredients.
    (Comment 27) One comment submitted in response to the 2015 Health 
Care Antiseptic PR stated its support for an industry comment submitted 
to the September 2014 NDAC meeting, which stated that the FDA proposed 
a safety testing program for OTC products similar to those required for 
new molecular entity or new chemical entity (NCE) review. The 
submission asserted that the active ingredients under the 1994 TFM are 
not NCEs and should not be subjected to requirements that surpass the 
requirements of a conventional NDA. The submission stated that, in 
FDA's proposal for the consumer antiseptic wash TFM, the 
unsubstantiated justification for additional safety data is stated as 
``new information regarding the potential risks from systemic 
absorption and long-term exposure to antiseptic active ingredients'' 
and the fact that exposure may be ``higher than previously thought,'' 
which, the submission argued, is not supported by information in the 
2013 Consumer Antiseptic Wash PR or in the docket.
    (Response 27) The assertion that the standards being proposed 
``surpass the requirements of a conventional NDA'' is incorrect. As an 
example, the MUsT has been required of topical NDA products approved 
since the early 1990s. Also, a MUsT is often necessary to assess 
absorption when a topical NDA product is reformulated. Whereas, for the 
health care antiseptic products under consideration in this rulemaking, 
once an active ingredient is determined to be GRASE for a particular 
indication, although in vitro testing would be required under the 
current framework, no further in vivo studies, including a MUsT, would 
be required unless in vitro testing suggests that substantially greater 
absorption may occur with a particular formulation.
3. Carcinogenicity Studies
    (Comment 28) Several comments asked FDA to reconsider the 
requirements for carcinogenicity studies, asserting that a good quality 
systemic carcinogenicity data set exists, along with in vitro genetic 
toxicology studies, for the majority of the active ingredients. The 
comments stated that it is unclear why FDA is requesting additional 
carcinogenicity studies for these ingredients. The comments also 
asserted that FDA should justify the requirement for additional 
carcinogenicity studies by the dermal route of exposure when a 
carcinogenicity study by the oral route exists because it is highly 
unlikely that systemic exposure would be higher from the dermal route 
of exposure than that resulting from the oral route of exposure. One 
comment requested that FDA focus on the ``health effects to be 
addressed in the safety assessment'' rather than establishing ``studies 
to be performed.'' Another comment stated that if inhalation 
carcinogenicity data are available, that such data may be used for 
worst-case exposure scenarios.
    (Response 28) The FDA is requesting dermal carcinogenicity 
assessment for these topically applied ingredients because the dose 
that the skin is exposed to following topical exposure can be much 
higher than the skin dose resulting from systemic exposure (81 FR 61106 
at 61123). FDA does not consider in vitro genetic toxicology studies to 
be a substitute for in vivo carcinogenicity studies. In addition, 
systemic exposure to the parent drug and metabolites can differ 
significantly in topically applied products, compared to orally 
administered products because the skin has its own metabolic capability 
(81 FR 61106 at 61123). Furthermore, the first-pass metabolism, which 
is available following oral exposure, is bypassed in the topical route 
of administration (81 FR 61106 at 61123) (Ref. 22). Dermal 
carcinogenicity studies, therefore, are not used solely to assess the 
effect of a drug on the skin tissue, but rather to evaluate the effect 
of topical exposure to all tissues of the treated animals.
4. Hormonal Effects
    (Comment 29) One comment agreed with the Agency that any 
toxicological risk assessment should consider whether, under conditions 
of use, an ingredient could cause adverse effects as a result of its 
ability to interfere with endocrine homeostasis. The comment also 
agreed with the Agency's statement that general and reproductive 
toxicology studies are generally adequate to identify potential 
hormonal effects. The comment urged FDA to take a flexible approach to 
measuring hormonal effects, and stated that any potential for hormonal 
effects can be addressed by the interpretation of repeat-dose or 
developmental and reproductive toxicity testing (DART) data. 
Specifically, the comment stated that FDA should emphasize that a 
repeat-dose DART study will provide the point of departure (e.g., 
NOAEL, Benchmark Dose Lower Bound of 10) for an ingredient that acts by 
an endocrine mode of action.
    (Response 29) We agree that data for hormonal effects can be 
gleaned from

[[Page 60495]]

previously conducted studies (chronic toxicity, DART, and 
multigenerational studies). As stated in the 2015 Health Care 
Antiseptic PR, data obtained from general nonclinical toxicity studies 
and reproductive/developmental studies, such as the repeat-dose 
toxicity, DART and carcinogenicity, are generally sufficient to 
identify potential hormonal effects in the developing offspring. We 
also stated that, if no signals are obtained from these studies, 
assuming the studies covered all the life stages (i.e., pregnancy, 
infancy, adolescence), then no further assessment of drug-induced 
hormonal effects are needed (80 FR 25166 at 25182 to 25183). However, 
if a positive response is seen in any of these animal studies that 
requires further investigation, additional studies, such as mechanistic 
studies, may be needed (Refs. 23, 24, and 25). In terms of the 
methodology used for the risk assessment of drug products, FDA does not 
follow the theoretical point of departure approach for assessing 
toxicological endpoints such as endocrine activity for drug products. 
Rather, FDA relies on the traditional NOAEL to identify a dose-response 
relationship in conducting its risk assessment (Refs. 26 and 27).
5. Resistance
    (Comment 30) Numerous comments on the issue of bacterial resistance 
were submitted in response to the 2015 Health Care Antiseptic PR. In 
general, the comments disagreed on whether antiseptics pose a public 
health risk from bacterial resistance. Some comments argued that the 
pervasive use of health care antiseptics poses an unacceptable risk for 
the development of resistance and that such products should be banned. 
Other comments argued that antiseptics do not pose such risks and 
criticized the data on which they believe FDA based its concerns.
    Specifically, several comments dismissed the in vitro data cited by 
FDA in the 2015 Health Care Antiseptic PR as not reflecting real-life 
conditions. The comments recommended that the most useful assessment of 
the risk of biocide resistance and cross-resistance to antibiotics are 
in situ studies, studies of clinical and environmental strains, or 
biomonitoring studies. Some comments asserted that studies of this type 
have reinforced the evidence that resistance and cross-resistance 
associated with antiseptics is a laboratory phenomenon observed only 
when tests are conducted under unrealistic conditions. One comment 
stated that there is little credible evidence that antiseptic products 
play any role in antibiotic resistance in human disease. The comment 
stated that, while some in vitro lab studies have been successful in 
forcing expression of resistance in some bacteria to antiseptic active 
ingredients, real world data from community studies using actual 
product formulations show no correlation between the use of such 
products and antibiotic resistance. The comment stated that further 
evidence of real world data showing no antimicrobial resistance 
development after the continued use of consumer products containing 
antimicrobial active compounds can be extracted from oral care clinical 
studies, which provide in vivo data, under well-controlled conditions, 
on exposure to antimicrobial-containing formulations over prolonged 
periods of time (e.g., 6 months to 5 years). Another comment cited the 
conclusions of an International Conference on Antimicrobial Research 
held in 2012 on a possible connection between biocide (antiseptic or 
disinfectant) resistance and antibiotic resistance to support the point 
that there is no correlation between antiseptic use and antibiotic 
resistance.
    (Response 30) As stated in the 2015 Health Care Antiseptic PR, we 
continue to believe that the development of bacteria that are resistant 
to antibiotics is an important public health issue, and additional data 
may tell us whether use of antiseptics in health care settings may 
contribute to the selection of bacteria that are less susceptible to 
both antiseptics and antibiotics (80 FR 25166 at 25183). Thus, we have 
conducted ingredient-specific reviews of the literature pertaining to 
antiseptic resistance and antibiotic cross-resistance, and determined 
that additional studies to assess the development of cross-resistance 
to antibiotics are needed for three of the deferred active 
ingredients--benzalkonium chloride, benzethonium chloride, and 
chloroxylenol. In the case of ethyl alcohol and isopropyl alcohol, 
sufficient data has been provided to assess the risk of antiseptic 
resistance and antibiotic cross-resistance.
    Laboratory studies have identified and characterized bacterial 
resistance mechanisms that confer a reduced susceptibility to 
antiseptics and, in some cases, antibiotics. Specifically, these data 
suggest that resistance development in the laboratory is very common 
for some active ingredients, such as benzethonium and benzalkonium 
chloride (Refs. 28, 29, 30, 31, and 32), and chloroxylenol (Refs. 33, 
34, 35, 36, 37, and 38). In contrast, resistance to other active 
ingredients, such as povidone-iodine (Refs. 39, 40, and 41) occurs 
infrequently in the laboratory setting. We acknowledge that 
observations made in the laboratory setting are not necessarily 
replicated in the real world setting. Therefore, we assessed additional 
studies performed in the clinical setting.
    Studies performed using clinical isolates found strong evidence of 
antiseptic resistance to benzethonium and benzalkonium chloride (Refs. 
42, 43, 44, 45, 46, 47, 48, 49, and 50). Antiseptic resistance genes 
qacA/B (Ref. 47) and qacE (Ref. 47) were identified and in 83 percent 
and 73 percent of the isolates tested, respectively, correlated with 
reduced susceptibility to benzalkonium and benzethonium chloride. In 
contrast, two studies published by Kawamura-Sato et al. (Refs. 51 and 
52) found the MIC of benzalkonium chloride for 283 clinical isolates to 
be well within in-use concentration.
    Only one clinical study could be found assessing resistance to 
chloroxylenol. Khor et al. (Ref. 53) collected samples from 
disinfectant solutions in hospitals. Of the chloroxylenol solutions 
tested, 42 percent had bacterial contamination. Isolation of these 
bacteria demonstrated that 81 percent were resistant to chloroxylenol, 
suggesting that these organisms have adapted to survival at 
concentrations which are usually bactericidal. Clinical studies 
assessing bacterial resistance to povidone-iodine were primarily 
negative (Refs. 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 
56, 57, 58, 59, 60, 61, 62, 63, and 64). Only one study, by Mycock et 
al. (Ref. 65), demonstrated resistance to povidone-iodine using 
clinical isolates, yet this study could not be repeated (Ref. 66). We 
believe that there is sufficient information to determine that exposure 
to povidone-iodine does not lead to the development of bacterial 
resistance, but additional data is necessary to assess this issue with 
regards to chloroxylenol.
    Other studies examined a possible correlation between antiseptic 
and antibiotic resistance (Refs. 38, 39, 40, 41, 42, 43, 44, 45, 46, 
47, 48, 49, 52, 53, 54, 55, 67, 68, 69, 70, 71, and 72). Comparisons 
suggest that alterations in the mean susceptibility of Staphylococcus 
aureus to antimicrobial biocides occurred between 1989 and 2000, but 
these changes were mirrored in both methicillin resistant and 
susceptible Staphylococcus aureus, suggesting that methicillin 
resistance has little to do with these changes (Ref. 72). In 
Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, 
several correlations (both positive and negative) between antibiotics 
and antimicrobial biocides

[[Page 60496]]

were found (Refs. 52, 54, 56, 67, 70, and 72). From the analyses of 
these clinical isolates, it is very difficult to support a hypothesis 
that increased biocide resistance is a cause of increased antibiotic 
resistance in these species.
    In general, studies have not clearly demonstrated an impact of 
antiseptic bacterial resistance mechanisms in the clinical setting. 
However, the available studies have limitations. As we noted in the 
2015 Health Care Antiseptic PR, studies in a clinical setting that we 
evaluated were limited by the small numbers and types of organisms, the 
brief time periods, and the locations examined. Bacteria expressing 
resistance mechanisms with a decreased susceptibility to antiseptics 
and some antibiotics have been isolated from a variety of natural 
settings (Refs. 73 and 74). Although the prevalence of antiseptic 
tolerant subpopulations in natural microbial populations is currently 
low, overuse of antiseptic active ingredients has the potential to 
select for resistant microorganisms.
    In sum, adequate data do not exist currently to determine whether 
the development of bacterial antiseptic resistance could also select 
for antibiotic resistant bacteria or how significant this selective 
pressure would be relative to the overuse of antibiotics, an important 
driver for antibiotic resistance. Moreover, the possible correlation 
between antiseptic and antibiotic resistance is not the only concern. 
Reduced antiseptic susceptibility may allow the persistence of 
organisms in the presence of low-level residues and contribute to the 
survival of antibiotic resistant organisms. Data are not currently 
available to assess the magnitude of this risk.
    (Comment 31) The comments also disagreed on the data needed to 
assess the risk of the development of resistance. One comment disagreed 
with the proposed testing described in the 2015 Health Care Antiseptic 
PR, arguing that there are no standard laboratory methods for 
evaluating the development of antimicrobial resistance. With regard to 
the recommendation for mechanism studies, they believed that it is 
unlikely that this kind of information can be developed for all active 
ingredients, particularly given that the mechanism(s) of action may be 
concentration dependent and combination/formulation effects may be 
highly relevant. The comments also believed that data characterizing 
the potential for transferring a resistance determinant to other 
bacteria is also an unrealistic requirement for a GRAS determination.
    Conversely, one comment recommended that antimicrobial resistance 
be addressed first through in vitro MIC determinations. The comment 
stated that, if an organism is shown to develop resistance rapidly, FDA 
should consider this information in its evaluation. The commenter 
believed that this test of the potential for the development of 
resistance is important because health care compliance with recommended 
use of health care antiseptic wash products is variable and products 
that result in the rapid development of antimicrobial resistance would 
pose a public health risk. The comment also asserted that GRAS/GRAE 
ingredients should pose little in the way of a resistance risk.
    (Response 31) In the 2015 Health Care Antiseptic PR, we described 
the data needed to help establish a better understanding of the 
interactions between antiseptic active ingredients in health care 
antiseptic products and bacterial resistance mechanisms and the data 
needed to provide the information necessary to perform an adequate risk 
assessment for these health care product uses. We suggested a tiered 
approach as an efficient means of developing data to address this 
resistance issue--beginning with laboratory studies aimed at evaluating 
the impact of exposure to nonlethal amounts of antiseptic active 
ingredients on antiseptic and antibiotic bacterial susceptibilities, 
along with additional data, if necessary, to help assess the likelihood 
that changes in susceptibility observed in the preliminary studies 
would occur in the health care setting (80 FR 25166 at 25183 to 25184).
    As we explained in the 2015 Health Care Antiseptic PR, we recognize 
that the science of evaluating the potential of compounds to cause 
bacterial resistance is evolving and acknowledged the possibility that 
alternative data may be identified as an appropriate substitute for 
evaluating resistance (80 FR 25166 at 25180). We also explained that we 
are aware that there are no standard protocols for these studies, but 
there are numerous publications in the literature of studies of this 
type that could provide guidance on the study design (Refs. 75, 76, and 
77).
    As explained in this document, we have deferred from this 
rulemaking six of the active ingredients used in health care antiseptic 
products, and we are discussing proposed protocols for the safety and 
effectiveness studies (Refs. 10, 11, 12, 13, 14, and 15). For those 
active ingredients for which resistance testing is required--
chloroxylenol, benzethonium chloride, and benzalkonium chloride--we 
have advised manufacturers, as an initial step, to conduct an active 
ingredient-specific literature review related to antiseptic resistance 
and antibiotic cross-resistance to assess the active ingredient's 
effect on development of cross-resistance to antiseptics and 
antibiotics in the health care setting, and to submit as much 
information and data as can be provided. If the literature review 
results show evidence of antiseptic or antibiotic resistance, 
additional studies may be necessary, consistent with the 
recommendations outlined in the 2015 Health Care Antiseptic PR (80 FR 
25166 at 25183 to 25184), to help assess the impact of the active 
ingredient on antiseptic and antibiotic susceptibilities. If, however, 
the literature review provides no evidence that the active ingredient 
affects antiseptic or antibiotic susceptibility, then it is likely that 
no further studies to address development of resistance will be needed 
to support a GRAS determination.
6. Other Safety Issues
    (Comment 32) One comment also stated that FDA's evaluation of risks 
associated with the extensive use of health care antiseptic soaps by 
health care workers should include the data from the Nurses' Health 
Studies (NHS), which are a series of long-term studies of health 
outcomes in several large cohorts of nurses. The comment asserted that 
these studies did not show any evidence that the use of topical health 
care antiseptics leads to adverse health outcomes in nurses. The 
comment concedes that the studies were not designed to evaluate risks 
associated with the use of antiseptic soaps, but still believes these 
studies are adequate to detect clinically-relevant health outcomes, 
including those associated with endocrine effects, that might arise 
from the use of antiseptic soaps.
    The comment also noted that the FDA's Safety Information and 
Adverse Event Reporting Program, MedWatch, did not have any safety-
related reports on the health care antiseptic products identified in 
the 2015 Health Care Antiseptic PR. In addition, the comment stated 
that FDA has not issued any safety alerts related to antiseptic skin 
products.
    (Response 32) FDA searched the NHS website cited in the comment, 
www.channing.harvard.edu/nhs/, and there did not appear to be any 
studies listed that specifically evaluated the health outcomes of 
nurses after using health care antiseptics. As the comment noted, the 
NHS studies were not designed to evaluate risks associated with the use 
of antiseptic soaps. In addition, in order to effectively evaluate the 
safety of an active ingredient or

[[Page 60497]]

drug, FDA uses data in which a control group is included in the study 
to compare to the treatment groups. A prospective NHS study evaluating 
the effect of exposure to the active ingredients in health care 
antiseptics would require a control group in which there is no exposure 
to health care antiseptic active ingredients. However, because all 
nurses in health care environments in which NHS studies have been 
conducted have to adhere to a universal hand washing protocol using 
antiseptic active ingredients, it is not possible to include a control 
group with no exposure to healthcare antiseptics in a NHS study.
    We also note that the safety signals FDA uses in making a GRAS 
determination, such as developmental and reproductive toxicity, 
carcinogenicity, or hormonal effects, would not likely be reported by 
consumers or health care professionals to MedWatch. Thus, the lack of 
MedWatch safety-related reports does not eliminate the need for the 
safety data outlined in the 2015 Health Care Antiseptic PR.
    (Comment 33) One comment stated that, for FDA to fully assess the 
safety of the health care topical antiseptic active ingredients, it 
must consider the impact of exposure on groups that may be particularly 
sensitive to exposure, including pregnant women, children, and the 
elderly, particularly with regards to chronic or highly sensitive 
(e.g., newborn infant) exposure.
    The comment also proposed that in classifying an ingredient as 
GRAS/GRAE, FDA should expand the health impacts (e.g., impact on the 
microbiome) and should consider ``clinically-relevant'' effectiveness 
(e.g., reduction of bacteria typically found in health care settings). 
The comment added that the final rule should incorporate safety 
standards to protect populations, outside of health care personnel, 
that could experience increased adverse events upon exposure to 
antiseptic products. The comment contended that the effect of 
antiseptic active ingredients on the microbiome should be more 
thoroughly considered in the final monograph to incorporate the effects 
into the benefit-to-risk calculation.
    The comment also asserted that data used in the safety evaluation 
of these ingredients should include metabolic parameters of disease 
states of individuals who would be chronically exposed to health care 
antiseptics in animal pharmacokinetic absorption, distribution, 
metabolism, and excretion (ADME) models.
    (Response 33) We agree that the impact of exposure to sensitive 
populations should be considered. Our paradigm of safety evaluation, 
which includes a battery of safety studies (ADME, MUsT, 
carcinogenicity, DART, and hormonal effects), can be used to establish 
a safety margin for potential safety signals in all populations, 
including sensitive ones.
    Currently, the effect of health care antiseptic active ingredients 
on the microbiome have not been included as a safety signal in 
classifying an active ingredient as GRAS or non-GRAS. FDA will continue 
to monitor emerging technologies that can help address safety signals 
for all of the products that it regulates, including products under the 
OTC topical antiseptic monograph.
    In addition, because there are many disease states which health 
care professionals or patients could have, it is not feasible to 
develop metabolic parameters for individual disease states in 
conducting the GRAS determinations of the active ingredients used in 
health care antiseptic products. Nor could one prospectively identify 
which specific metabolic parameters should be tracked, or if there were 
defined levels of changes in each parameter that would be of concern.
    (Comment 34) Another comment stated that FDA needs to address the 
impact of inactive ingredients and final formulations on the safety 
assessments of health care antiseptic products.
    (Response 34) Testing requirements for the final product 
formulations, which would require exposure to both active and inactive 
ingredients, are not addressed in this final rule because none of the 
active ingredients that are the subject of this final rule are 
considered GRAS/GRAE for use in health care antiseptic products, given 
the lack of sufficient effectiveness and safety data submitted for 
these ingredients. The testing requirements for final formulations of 
products containing the six deferred active ingredients will be 
addressed, if applicable, after a decision is made regarding the 
monograph status of those ingredients.
    (Comment 35) One comment indicated that the cost of conducting 
safety studies is expensive and asserted that the testing requirements 
run counter to the spirit of the OTC monograph. The comment proposed 
that the safety studies, should therefore, be conducted by academic and 
National Institutes of Health (NIH) investigators.
    (Response 35) The monograph process is public in nature and studies 
may be conducted by any interested parties, including academics and NIH 
investigators. FDA is willing to review all relevant available data in 
order to reach a final determination of safety and effectiveness. 
Ultimately, manufacturers are responsible for the safety and 
effectiveness of the drug products they market.
    (Comment 36) One comment contended that NDA products, such as 
Avagard (1 percent chlorhexidine gluconate, 62 percent ethyl alcohol) 
should be subject to the safety standards proposed in the 2015 Health 
Care Antiseptic PR.
    (Response 36) FDA regulates NDA products under a different 
regulatory pathway than the OTC drug monograph products, such as the 
OTC health care antiseptics that are the subject of this rulemaking. We 
consider safety criteria for both monograph and NDA products. The 
review of an individual product under an NDA may warrant a different 
assessment than a group of active ingredients used in a range of 
products.

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

    (Comment 37) Several comments raised issues concerning the 
preliminary regulatory impact analysis and the Agency's assessment of 
the net benefit of the rulemaking.
    (Response 37) Our response is provided in the full discussion of 
economic impacts, available in the docket for this rulemaking (Docket 
No. FDA-2015-N-0101, (Ref. 78), https://www.regulations.gov) and at 
https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

VI. Ingredients Not Generally Recognized as Safe and Effective

    No additional safety or effectiveness data have been submitted to 
support a GRAS/GRAE determination for the non-deferred health care 
antiseptic active ingredients described in this rule. Thus, the 
following active ingredients are not GRAS/GRAE for use as a health care 
antiseptic:

 Chlorhexidine gluconate
 Cloflucarban
 Fluorosalan
 Hexachlorophene
 Hexylresorcinol
 Iodophors (Iodine-containing ingredients)
[cir] Iodine complex (ammonium ether sulfate and polyoxyethylene 
sorbitan monolaurate)
[cir] Iodine complex (phosphate ester of alkylaryloxy polyethylene 
glycol)
[cir] Iodine tincture USP
[cir] Iodine topical solution USP
[cir] Nonylphenoxypoly (ethyleneoxy) ethanoliodine

[[Page 60498]]

[cir] Poloxamer--iodine complex
[cir] Undecoylium chloride iodine complex
 Mercufenol chloride
 Methylbenzethonium chloride
 Phenol
 Secondary amyltricresols
 Sodium oxychlorosene
 Tribromsalan
 Triclocarban
 Triclosan
 Triple dye
 Combination of calomel, oxyquinoline benzoate, 
triethanolamine, and phenol derivative
 Combination of mercufenol chloride and secondary 
amyltricresols in 50 percent alcohol

    Accordingly, OTC health care antiseptic drug products containing 
these active ingredients will require approval under an NDA or ANDA 
prior to marketing.

VII. Compliance Date

    In the 2015 Health Care Antiseptic PR, we recognized, based on the 
scope of products subject to this final rule, that manufacturers would 
need time to comply with this final rule. Thus, as proposed in the 2015 
Health Care Antiseptic PR (80 FR 25166 at 25195), this final rule will 
be effective 1 year after the date of the final rule's publication in 
the Federal Register. On or after that date, any OTC health care 
antiseptic drug products containing an ingredient that we have found in 
this final rule to be not GRAS/GRAE cannot be introduced or delivered 
for introduction into interstate commerce unless it is the subject of 
an approved NDA or ANDA.

VIII. Summary of Regulatory Impact Analysis

    The summary analysis of benefits and costs included in this final 
rule is drawn from the detailed Regulatory Impact Analysis that is 
available at https://www.regulations.gov, Docket No. FDA-2015-N-0101, 
(Ref. 78).

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 13771, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 
13563 direct us to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Executive Order 13771 
requires that the costs associated with significant new regulations 
``shall, to the extent permitted by law, be offset by the elimination 
of existing costs associated with at least two prior regulations.'' We 
believe that this final rule is a significant regulatory action as 
defined by Executive Order 12866. This final rule is considered an 
Executive Order 13771 regulatory action.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because we estimate that only four small businesses will be 
adversely affected by the final rule, we certify that the final rule 
will not have a significant economic impact on a substantial number of 
small entities.
    The Unfunded Mandates Reform Act of 1995 (Section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $148 million, using the most current (2016) Implicit 
Price Deflator for the Gross Domestic Product. This final rule would 
not result in an expenditure in any year that meets or exceeds this 
amount

B. Summary of Costs and Benefits

    As discussed in the preamble of this final rule, this rule 
establishes that 24 eligible active ingredients are not generally 
recognized as safe and effective for use in 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 addressed in the health care antiseptic proposed 
rule: Benzalkonium chloride, benzethonium chloride, chloroxylenol, 
ethyl alcohol, isopropyl alcohol, and povidone-iodine. This final rule 
also addresses the eligibility of three active ingredients--alcohol 
(ethyl alcohol, see section V.C.3), 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 (see section IV.D.1, table 3). 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 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, plus the 
lost producer surplus (measured as lost revenues) due to removing one 
alcohol surgical hand scrub from the market. 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.
    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. The full analysis of economic 
impacts is available in docket FDA-2015-N-0101 (Ref. 78) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

[[Page 60499]]

[GRAPHIC] [TIFF OMITTED] TR20DE17.001


                                  Table 5--Executive Order 13771 Summary Table
                           [In $ millions 2016 dollars, over an infinite time horizon]
----------------------------------------------------------------------------------------------------------------
                                                                                    Lower bound     Upper bound
                                                                   Primary (7%)        (7%)            (7%)
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------

IX. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by OMB under the Paperwork Reduction Act of 1995 is not 
required.

X. Analysis of Environmental Impact

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

XI. Federalism

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

[[Page 60500]]

of this rule are consistent with Executive Order 13132.

XII. References

    The following references are on display at the office of the 
Dockets Management Staff (see ADDRESSES) and are available for viewing 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they are also available electronically at https://www.regulations.gov. 
FDA has verified all website addresses, as of the date of this document 
publishes in the Federal Register, but websites are subject to change 
over time.

1. Transcript of the January 22, 1997, Joint Meeting of the 
Nonprescription Drugs and Anti-Infective Drugs Advisory Committees, 
OTC Vol. 230002. Available at https://www.regulations.gov/document?D=FDA-2015-N-0101-0008.
2. Comment submitted in Docket No. FDA-1975-N-0012-0081. Available 
at https://www.regulations.gov/document?D=FDA-1975-N-0012-0081.
3. Transcript of the March 23, 2005, Nonprescription Drugs Advisory 
Committee. Available at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4098T1.htm.
4. Transcript of the September 3, 2014, Meeting of the 
Nonprescription Drugs Advisory Committee 2014. Available at https://wayback.archive-it.org/7993/20170404152741/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM421121.pdf.
5. Part 130-New Drugs, Procedures for Classification of Over-the-
Counter Drugs. Available at http://www.ecfr.gov/cgi-bin/text-idx?SID=34d4a9d52dbac32a09a126a1dd44ef47&mc=true&node=se21.5.330_110&rgn=div8.
6. Tuuli, M.G., et al., A Randomized Trial Comparing Skin Antiseptic 
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39. Block, C., et al., Evaluation of Chlorhexidine and Povidone 
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41. Lacey, R.W., et al., Antiseptic Resistance in Methicillin-
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1985. Available at https://www.ncbi.nlm.nih.gov/pubmed/2866372.
42. Liu, Q., et al., Sensitivities to Biocides and Distribution of 
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Staphylococcus aureus Isolated in a Teaching Hospital, Scandinavian 
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43. Furi, L., et al., Evaluation of Reduced Susceptibility to 
Quaternary Ammonium Compounds and Bisbiguanides in Clinical Isolates 
and Laboratory-Generated Mutants of Staphylococcus aureus, 
Antimicrobial Agents and Chemotherapy, 57(8): p. 3488-97, 2013. 
Available at http://www.ncbi.nlm.nih.gov/pubmed/23669380.
44. Babaei, M., et al., Extremely High Prevalence of Antiseptic 
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p. 11, 2015. Available at https://www.ncbi.nlm.nih.gov/pubmed/25858356.
45. Ghasemzadeh-Moghaddam, H., et al., Methicillin-Susceptible and -
Resistant Staphylococcus aureus With High-Level Antiseptic and Low-
Level Mupirocin Resistance in Malaysia, Microbial Drug Resistance, 
20(5): p. 472-77, 2014. Available at https://www.ncbi.nlm.nih.gov/pubmed/24841796.
46. Noguchi, N., et al., Susceptibilities to Antiseptic Agents and 
Distribution of Antiseptic-Resistance Genes qacA/B and smr of 
Methicillin-Resistant Staphylococcus aureus isolated in Asia During 
1998 and 1999, Journal of Medical Microbiology, 54(1): p. 557-65, 
2005. Available at https://www.ncbi.nlm.nih.gov/pubmed/15888465.
47. Shamsudin, M.N., et al., High Prevalence of qacA/B Carriage 
Among Clinical Isolates of Meticillin-Resistant Staphylococcus 
aureus in Malaysia, Journal of Hospital Infection, 81(3): p. 206-8, 
2012. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=22633074.
48. Weber, D.J. and W.A. Rutala, Use of Germicides in the Home and 
the Healthcare Setting: Is There a Relationship between Germicide 
Use and Antibiotic Resistance?, Infection Control and Hospital 
Epidemiology, 27(10): p. 1107-19, 2006. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=17006819.
49. Rajamohan, G., et al., Biocide-Tolerant Multidrug-Resistant 
Acinetobacter baumannii Clinical Strains Are Associated with Higher 
Biofilm Formation, Journal of Hospital Infection, 73(3): p. 287-89, 
2009. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=19762119.
50. Akinkunmi, E.O. and A. Lamikanra, Susceptibility of Community 
Associated Methicillin Resistant Staphylococcus aureus Isolated From 
Faeces to Antiseptics, Journal of Infection in Developing Countries, 
6(4): p. 317-23, 2012. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=22505440.
51. Kawamura-Sato, K., et al., Reduction of Disinfectant 
Bactericidal Activities in Clinically Isolated Acinetobacter species 
in the Presence of Organic Material, Journal of Antimicrobial 
Chemotherapy, 61(3): p. 568-76, 2008. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=18192683.
52. Kawamura-Sato, K., et al., Correlation Between Reduced 
Susceptibility to Disinfectants and Multidrug Resistance Among 
Clinical Isolates of Acinetobacter Species, Journal of Antimicrobial 
Chemotherapy, 65(9): p. 1975-83, 2010. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=20576639.
53. Khor, S.Y. and M. Jegathesan, In-Use testing of Disinfectants in 
Malaysian Government Hospitals, Medical Journal of Malaysia, 32(1): 
p. 85-89, 1977. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=609352.
54. Rikimaru, T., et al., Bactericidal Activities of Commonly Used 
Antiseptics Against Multidrug-Resistant Mycobacterium tuberculosis, 
Dermatology, 204(Supp): p. 15-20, 2002. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=12011515.
55. Lanker Klossner, B., et al., Nondevelopment of Resistance by 
Bacteria During Hospital Use of Povidone-Iodine, Dermatology, 
195(Supp 2): p. 10-13, 1997. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=9403249.
56. Prince, H.N., et al., Drug Resistance Studies with Topical 
Antiseptics, Journal of Pharmaceutical Sciences, 67(11): p. 1629-31, 
1978. Available at https://www.ncbi.nlm.nih.gov/pubmed/712607.
57. Wiegand, C., et al., Analysis of the Adaptation Capacity of 
Staphylococcus aureus to Commonly Used Antiseptics by Microplate 
Laser Nephelometry, Skin Pharmacology and Physiology, 25(6): p. 288-
97, 2012. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=22890487.
58. Giacometti, A., et al., Antiseptic Compounds Still Active 
Against Bacterial Strains Isolated From Surgical Wound Infections 
Despite Increasing Antibiotic Resistance, European Journal of 
Clinical Microbiology and Infectious Diseases, 21(7): p. 553-56, 
2002. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=12172750.
59. Gocke, D.J., et al., In Vitro Studies of the Killing of Clinical 
Isolates by Povidone-

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Iodine Solutions, Journal of Hospital Infection, 6(Supp A): p. 59-
66, 1985. Available at http://www.ncbi.nlm.nih.gov/pubmed/2860177.
60. Yasuda, T., et al., Comparison of Bactericidal Activities of 
Various Disinfectants Against Methicillin-Sensitive Staphylococcus 
aureus and Methicillin-Resistant Staphylococcus aureus, Postgraduate 
Medical Journal, 69(Supp 3): p. 66-69, 1993. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=8290461.
61. Gordon, J. and A.R. Mclure, In-Vitro Comparison of Bactericidal 
Activity of Povidone-Iodine and Chlorhexidine Against Methicillin-
Resistant Staphylococcus aureus, Surgical Research Communications, 
5(4): p. 313-14, 1989. Available at http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L19121090.
62. Barry, A.L., et al., Lack of Effect of Antibiotic Resistance on 
Susceptibility of Microorganisms to Chlorhexidine Gluconate or 
Povidone Iodine, European Journal of Clinical Microbiology and 
Infectious Diseases, 18(12): p. 920-21, 1999. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=10691210.
63. Rikimaru, T., et al., Efficacy of Common Antiseptics Against 
Multidrug-Resistant Mycobacterium tuberculosis, International 
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Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=12234131.
64. Sakuragi, T., et al., Bactericidal Activity of Skin 
Disinfectants on Methicillin-Resistant Staphylococcus aureus, 
Anesthesia and Analgesia, 81(3): p. 555-58, 1995. Available at 
http://www.ncbi.nlm.nih.gov/pubmed/7653822.
65. Sanchez, P., et al., The Biocide Triclosan Selects 
Stenotrophomonas maltophilia Mutants That Overproduce the SmeDEF 
Multidrug Efflux Pump, Antimicrobial Agents and Chemotherapy, 49(2): 
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66. Payne, D.N., et al., Antiseptics: A Forgotten Weapon in the 
Control of Antibiotic Resistant Bacteria in Hospital and Community 
Settings?, Journal of the Royal Society of Health, 118(1): p. 18-22, 
1998. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=9724934.
67. Oggioni, M.R., et al., Significant Differences Characterize the 
Correlation Coefficients Between Biocide and Antibiotic 
Susceptibility Profiles in Staphylococcus aureus, Current 
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https://www.ncbi.nlm.nih.gov/pubmed/?term=25760337.
68. Coelho, J.R., et al., The Use of Machine Learning Methodologies 
to Analyse Antibiotic and Biocide Susceptibility in Staphylococcus 
aureus, PLoS One, 8(2): p. 1, 2013. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=23431361.
69. Stickler, D.J., et al., Antiseptic and Antibiotic Resistance in 
Gram-Negative Bacteria Causing Urinary Tract Infection in Spinal 
Cord Injured Patients, Paraplegia, 19(1): p. 50-58, 1981. Available 
at https://www.ncbi.nlm.nih.gov/pubmed/7220061.
70. Buffet-Bataillon, S., et al., Effect of Higher Minimum 
Inhibitory Concentrations of Quaternary Ammonium Compounds in 
Clinical E. coli Isolates on Antibiotic Susceptibilities and 
Clinical Outcomes, Journal of Hospital Infection, 79(2): p. 141-46, 
2011. Available at http://www.ncbi.nlm.nih.gov/pubmed/21807440.
71. Shi, G.S., et al., Prevalence of Antiseptic-Resistance Genes in 
Staphylococci Isolated from Orthokeratology Lens and Spectacle 
Wearers in Hong Kong, Investigative Ophthalmology and Visual 
Science, 56(5): p. 3069-74, 2015. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=25788652.
72. Lambert, R.J., Comparative Analysis of Antibiotic and 
Antimicrobial Biocide Susceptibility Data in Clinical Isolates of 
Methicillin-Sensitive Staphylococcus aureus, Methicillin-Resistant 
Staphylococcus aureus and Pseudomonas aeruginosa between 1989 and 
2000, Journal of Applied Microbiology, 97(4): p. 699-711, 2004. 
Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=15357719.
73. Morrissey, I., et al., Evaluation of Epidemiological Cut-Off 
Values Indicates That Biocide Resistant Subpopulations Are Uncommon 
in Natural Isolates of Clinically-Relevant Microorganisms, PLoS One, 
9(1): p. 86669, 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24466194.
74. Copitch, J.L., et al., Prevalence of Decreased Susceptibility to 
Triclosan in Salmonella enterica Isolates from Animals and Humans 
and Association with Multiple Drug Resistance, International Journal 
of Antimicrobial Agents, 36(3): p. 247-51, 2010. Available at 
https://www.ncbi.nlm.nih.gov/pubmed/?term=20541914.
75. Braoudaki, M. and A.C. Hilton, Adaptive Resistance to Biocides 
in Salmonella enterica and Escherichia coli O157 and Cross-
Resistance to Antimicrobial Agents, Journal of Clinical 
Microbiology, 42(1): p. 73-78, 2004. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=14715734.
76. Langsrud, S., et al., Cross-Resistance to Antibiotics of 
Escherichia coli Adapted to Benzalkonium Chloride or Exposed to 
Stress-Inducers, Journal of Applied Microbiology, 96(1): p. 201-08, 
2004. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=14678175.
77. Joynson, J.A., et al., Adaptive Resistance to Benzalkonium 
Chloride, Amikacin and Tobramycin: The Effect on Susceptibility to 
Other Antimicrobials, Journal of Applied Microbiology, 93(1): p. 96-
107, 2002. Available at https://www.ncbi.nlm.nih.gov/pubmed/?term=12067378.
78. FDA Regulatory Impact Analysis, Safety and Effectiveness for 
Health Care Antiseptics; Topical Antimicrobial Drug Products for 
Over-the-Counter Human Use. Available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310 is amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for part 310 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-l; 42 U.S.C. 
216, 241, 242(a), 262.

0
2. Amend Sec.  310.545 as follows:
0
a. Add reserved paragraphs (a)(27)(v), (vii), and (ix);
0
b. Add paragraphs (a)(27)(vi), (viii), and (x);
0
c. In paragraph (d) introductory text, remove ``(d)(41)'' and in its 
place add ``(42)''; and
0
d. Add paragraph (d)(42).
    The additions read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (27) * * *
    (v) [Reserved]
    (vi) Health care personnel hand wash drug products. Approved as of 
December 20, 2018.

Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan 
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex

    (vii) [Reserved]
    (viii) Surgical hand scrub drug products. Approved as of December 
20, 2018.


[[Page 60503]]


Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan 
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex

    (ix) [Reserved]
    (x) Patient antiseptic skin preparation drug products. Approved as 
of December 20, 2018.

Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture (USP)
Iodine topical solution (USP)
Mercufenol chloride
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple dye
Undecoylium chloride iodine complex
Combination of calomel, oxyquinoline benzoate, triethanolamine, and 
phenol derivative
Combination of mercufenol chloride and secondary amyltricresols in 50 
percent alcohol
* * * * *
    (d) * * *
    (42) December 20, 2018, for products subject to paragraphs 
(a)(27)(vi) through (x) of this section.

    Dated: December 14, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-27317 Filed 12-19-17; 8:45 am]
 BILLING CODE 4164-01-P