[Federal Register Volume 80, Number 84 (Friday, May 1, 2015)]
[Proposed Rules]
[Pages 25165-25205]
[FR Doc No: 2015-10174]

Vol. 80

Friday,

No. 84

May 1, 2015

Part V

 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; Proposed
Amendment of the Tentative Final Monograph; Reopening of Administrative
Record; Proposed Rule

Federal Register / Vol. 80 , No. 84 / Friday, May 1, 2015 / Proposed
Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2015-N-0101] (Formerly Docket No. FDA-1975-N-0012)
RIN 0910-AF69

Safety and Effectiveness of Health Care Antiseptics; Topical
Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed
Amendment of the Tentative Final Monograph; Reopening of Administrative
Record

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this
proposed rule to amend the 1994 tentative final monograph or proposed
rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug
products. In this proposed rule, we are proposing to establish
conditions under which OTC antiseptic products intended for use by
health care professionals in a hospital setting or other health care
situations outside the hospital are generally recognized as safe and
effective. In the 1994 TFM, certain antiseptic active ingredients were
proposed as being generally recognized as safe for use in health care
settings based on safety data evaluated by FDA as part of its ongoing
review of OTC antiseptic drug products. However, in light of more
recent scientific developments, we are now proposing that additional
safety data are necessary to support the safety of antiseptic active
ingredients for these uses. We also are proposing that all health care
antiseptic active ingredients have in vitro data characterizing the
ingredient's antimicrobial properties and in vivo clinical simulation
studies showing that specified log reductions in the amount of certain
bacteria are achieved using the ingredient.

DATES: Submit electronic or written comments by October 28, 2015. See
section VIII of this document for the proposed effective date of a
final rule based on this proposed rule.

ADDRESSES: You may submit comments by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Docket No.
FDA-2015-N-0101 (formerly Docket No. FDA-1975-N-0012) and RIN 0910-AF69
for this rulemaking. All comments received may be posted without change
to http://www.regulations.gov, including any personal information
provided.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Earlier FDA publications, public submissions, and other materials
relevant to this rulemaking may also be found under Docket No. FDA-
1975-N-0012 (formerly Docket No. 1975N-0183H) using the same
procedures.

FOR FURTHER INFORMATION CONTACT: Michelle M. Jackson, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5411, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Regulatory Action

    FDA is proposing to amend the 1994 TFM for OTC antiseptic drug
products that published in the Federal Register of June 17, 1994 (59 FR
31402). The 1994 TFM is part of FDA's ongoing rulemaking to evaluate
the safety and effectiveness of OTC drug products marketed in the
United States on or before May 1972 (OTC Drug Review).
    FDA is proposing to establish new conditions under which OTC health
care antiseptic active ingredients are generally recognized as safe and
effective (GRAS/GRAE) based on FDA's reevaluation of the safety and
effectiveness data requirements proposed in the 1994 TFM in light of
comments received, input from subsequent public meetings, and our
independent evaluation of other relevant scientific information we have
identified and placed in the administrative file. These health care
antiseptic products include health care personnel hand washes, health
care personnel hand rubs, surgical hand scrubs, surgical hand rubs, and
patient preoperative skin preparations.

Summary of the Major Provisions of the Regulatory Action in Question

    We are proposing that additional safety and effectiveness data are
necessary to support a GRAS/GRAE determination for OTC antiseptic
active ingredients intended for use by health care professionals. The
effectiveness data, the safety data, and the effect on the previously
proposed classification of active ingredients are described briefly in
this summary.

Effectiveness

    A determination that a drug product containing a particular active
ingredient would be generally recognized as effective (GRAE) for a
particular intended use requires consideration of the benefit-to-risk
ratio for the drug for that use. New information on potential risks
posed by the use of certain health care antiseptic products, as well as
input from the Nonprescription Drugs Advisory Committee (NDAC) that met
in March 2005 (the March 2005 NDAC), has prompted us to reevaluate the
data needed for classifying health care antiseptic active ingredients
as GRAE (see new information described in the Safety section of this
summary). We continue 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 ingredient. However, the log
reductions required for the demonstration of effectiveness for health
care antiseptics have been revised based on the recommendations of the
March 2005 NDAC, comments received after the 1994 TFM, and other
information that FDA reviewed.
    We have evaluated the available literature and the data and other
information that were submitted to the rulemaking on the effectiveness
of health care antiseptic active ingredients, as well as the
recommendations from the public meetings held by the Agency on
antiseptics. We propose that the record should contain additional log
reduction data to demonstrate the effectiveness of health care
antiseptic active ingredients.

Safety

    Several important scientific developments that affect the safety
evaluation of these ingredients have occurred since FDA's 1994
evaluation of the safety of health care antiseptic active ingredients
under the OTC Drug

Review. Improved analytical methods now exist that can detect and more
accurately measure these active ingredients at lower levels in the
bloodstream and tissue. Consequently, we now know that, at least for
certain health care antiseptic ingredients, systemic exposure is higher
than previously thought (Refs. 1 through 5), and new information is
available about the potential risks from systemic absorption and long-
term exposure. New safety information also suggests that widespread
antiseptic use could have an impact on the development of bacterial
resistance. Currently, the significance of this new information is not
known and we are unaware of any information that would lead us to
conclude that any health care antiseptic active ingredient is unsafe
(other than those that we proposed to be Category II in the 1994 TFM).
The benefits of any active ingredient will need to be weighed against
its risks once both the effectiveness and safety have been better
characterized to determine GRAS/GRAE status.
    The previously proposed generally recognized as safe (GRAS)
determinations were based on safety principles that have since evolved
significantly because of advances in technology, development of new
test methods, and experience with performing test methods. The standard
battery of tests that were used to determine the safety of drugs has
changed over time to incorporate improvements in safety testing. To
ensure that health care antiseptic active ingredients are GRAS, data
that meet current safety standards are needed.
    Based on these developments, we are now proposing that additional
safety data are needed for each health care antiseptic active
ingredient to support a GRAS classification. The data described in this
proposed rule are the minimum data necessary to establish the safety of
antiseptic active ingredients used in health care antiseptic products
in light of the new safety information. Health care practitioners may
use health care antiseptics on a daily, long-term (i.e., chronic)
basis. Patient preoperative skin preparations, on the other hand, are
not usually used on any single patient on a daily basis. Nevertheless,
an individual may be exposed to patient preoperative skin preparations
(particularly those used for preinjection skin preparation) enough
times over a lifetime to be considered a chronic use. The data we
propose are 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 use trials 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 emphasize that our proposal for more safety and effectiveness
data for health care antiseptic active ingredients does not mean that
we believe that health care antiseptic products containing these
ingredients are ineffective or unsafe, or that their use should be
discontinued. However, now that we have enhanced abilities to measure
and evaluate the safety and effectiveness of these ingredients, we
believe we should obtain relevant data to support a GRAS/GRAE
determination. Consequently, based on new information and improvements
in safety testing and in our understanding of log reduction testing and
the use of surrogate endpoints since our 1994 evaluation, we are
requesting more safety and effectiveness data to ensure that these
health care antiseptic active ingredients meet the updated standards to
support a GRAS/GRAE classification. Considering the prevalent use of
health care antiseptic products in health care settings, it is critical
that the safety and effectiveness of these ingredients be supported by
data that meet the most current standards.

Active Ingredients

    In the 1994 TFM, 27 antiseptic active ingredients were classified
for three OTC health care antiseptic uses: (1) Patient preoperative
skin preparation, (2) health care personnel hand wash, and (3) surgical
hand scrub (59 FR 31402 at 31435) (for a list of all active ingredients
covered by this proposed rule, see tables 4 through 7). Our detailed
evaluation of the effectiveness and safety of the active ingredients
for which data were submitted can be found in sections VI.A and VII.D.
In the 1994 TFM, alcohol (60 to 95 percent) and povidone-iodine (5 to
10 percent), which are active ingredients that are being evaluated for
use as a health care antiseptic in this proposed rule, were proposed to
be classified as GRAS/GRAE (59 FR 31402 at 31435-31436) for patient
preoperative skin preparation, health care personnel hand wash, and
surgical hand scrub. Iodine tincture, iodine topical solution, and
isopropyl alcohol were proposed to be classified as GRAS/GRAE for
patient preoperative skin preparations (59 FR 31402 at 31435-31436).
However, we now propose that the health care antiseptic active
ingredients classified as GRAS/GRAE for use in health care antiseptics
in the 1994 TFM need additional safety and effectiveness data to
support a classification of GRAS/GRAE for health care antiseptic use.
    Several health care antiseptic active ingredients evaluated in the
1994 TFM were proposed as GRAS, but not GRAE, for use in health care
antiseptics because they lacked sufficient evidence of effectiveness
for health care use (see tables 4 and 5). We are now proposing that
these ingredients need additional safety data, as well as effectiveness
data, to be classified as GRAS/GRAE.
    The data available and the data that are missing are discussed
separately for each active ingredient in this proposed rule. For those
ingredients for which no data have been submitted since the 1994 TFM,
we have not included a separate discussion section, but have indicated
in table 10 that no additional data were submitted or identified.
    In certain cases, manufacturers may have the data we propose as
necessary in this proposed rule, but to date these data have not been
submitted to the OTC Drug Review. Although currently we expect to
receive the necessary data, if we do not obtain sufficient data to
support monograph conditions for health care antiseptic products
containing these active ingredients, these products may not be included
in the future OTC health care antiseptic final monograph. Any health
care antiseptic product containing the active ingredients being
considered under this rulemaking that are not included in a future
final monograph could obtain approval to market by submitting new drug
applications (NDAs) under section 505 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 355). After a final monograph is
established, these products might be able to submit NDA deviations in
accordance with Sec.  330.11 (21 CFR 330.11), limiting the scope of
review necessary to obtain approval.

Costs and Benefits

    Benefits represent the monetary values associated with reducing the
potential adverse health effects associated with the use of health care
antiseptic products containing active ingredients that could
potentially be shown to be unsafe or ineffective for their intended
use. We estimate annual benefits to roughly range between $0 and $0.16
million. Total upfront costs are estimated to range between $64 and
$90.8 million. Annualizing these costs over a 10-year period, we
estimate total annualized costs to range from $7.3 and $10.4 million at
a 3 percent discount

rate to $8.5 and $12.1 million at a 7 percent discount rate. Potential
one-time costs include the expenditures to conduct various safety and
effectiveness tests, and to reformulate and relabel products that
contain nonmonograph ingredients.

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                                            Total benefits       Total costs annualized
 Summary of costs and benefits of the     annualized over 10       over 10 years  (in      Total one-time costs
            proposed rule                years  (in millions)          millions)              (in millions)
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    Total............................  $0.0 to $0.16..........  $7.3 to $10.4 at (3%)..  $64.0 to $90.8
                                                                $8.5 to $12.1 at (7%)..
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Table of Contents

I. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Proposed Rule Covers Only Health Care Antiseptics
    D. Comment Period
II. Background
    A. Significant Rulemakings Relevant to This Proposed Rule
    B. Public Meetings Relevant to This Proposed Rule
    C. Comments Received by FDA
III. Active Ingredients With Insufficient Evidence of Eligibility
for the OTC Drug Review
    A. Eligibility for the OTC Drug Review
    B. Eligibility of Certain Active Ingredients for Certain Health
Care Antiseptic Uses Under the OTC Drug Review
IV. Ingredients Previously Proposed as Not Generally Recognized as
Safe and Effective
V. Summary of Proposed Classifications of OTC Health Care Antiseptic
Active Ingredients
VI. Effectiveness (Generally Recognized as Effective) Determination
    A. Evaluation of Effectiveness Data
    B. Current Standards: Studies Needed to Support a Generally
Recognized as Effective Determination
VII. Safety (Generally Recognized as Safe) Determination
    A. New Issues
    B. Antimicrobial Resistance
    C. Studies to Support a Generally Recognized as Safe
Determination
    D. Review of Available Data for Each Antiseptic Active
Ingredient
VIII. Proposed Effective Date
IX. Summary of Preliminary Regulatory Impact Analysis
    A. Introduction
    B. Summary of Costs and Benefits
X. Paperwork Reduction Act of 1995
XI. Environmental Impact
XII. Federalism
XIII. References

I. Introduction

    In the following sections, we provide a brief description of
terminology used in the OTC Drug Review regulations and an overview of
OTC topical antiseptic drug products, and then describe in more detail
the OTC health care antiseptics that are the subject of this proposed
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), the September 1974 advance notice of proposed
rulemaking (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),
and in the Federal Register of June 17, 1994 (59 FR 31402) (the 1994
TFM), were each designated as a ``tentative final monograph.'' The
present proposed rule, which is a reproposal regarding health care
antiseptic drug products, is also designated as a ``tentative final
monograph.''
2. Category I, II, and III Classifications
    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). Section 330.10 provides that any testing necessary to
resolve the safety or effectiveness issues that formerly resulted in a
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, this proposed rule (at the
tentative final monograph stage) retains the concepts of Categories I,
II, and III.
    At the final monograph stage, FDA does not use the terms ``Category
I,'' ``Category II,'' and ``Category III.'' In place of Category I, the
term ``monograph conditions'' is used; in place of Categories II and
III, the term ``nonmonograph conditions'' is used.

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. In 1974, the Agency published an ANPR for topical antimicrobial
products that encompassed products for both health care and consumer
use (39 FR 33103, September 13, 1974). The 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 the first aid
antiseptics in the Federal Register of July 22, 1991 (56 FR 33644)
(1991 First Aid TFM). Thus, first aid antiseptics are not discussed
further in this document.
    The four remaining categories of topical antimicrobials were
addressed in the 1994 TFM. 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). Antiseptics for
use by the food industry are not discussed further in this document.
    As we proposed in the consumer antiseptic wash proposed rule
published in the Federal Register of December 17, 2013 (78 FR 76444)
(the Consumer Wash PR), our evaluation of OTC antiseptic drug products
is being further subdivided into health care antiseptics and consumer
antiseptics. We believe that these categories are distinct based on the
proposed use setting, target population, and the fact

that each setting presents a different level of risk for infection. For
example, in health care settings, the patient population is generally
more susceptible to infection than the general U.S. consumer population
(i.e., the population who use consumer antiseptic washes).
Consequently, in the health care setting, the potential for spread of
infection and the potential for serious outcomes of infection may be
relatively higher than in the U.S. consumer setting. Therefore, the
safety and effectiveness should be evaluated separately for each
intended use to support a GRAS/GRAE determination.
    Health care antiseptics are drug products intended for use by
health care professionals in a hospital setting or other health care
situations outside the hospital. Patient preoperative skin
preparations, which include products that are used for preparation of
the 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 at home or at other locations and use patient preoperative
skin preparations prior to injection. In 1974, when the ANPR (39 FR
33103) to establish an OTC topical antimicrobial monograph was
published in the Federal Register, antimicrobial soaps used by
consumers were distinct from professional use antiseptics, such as
health care personnel hand washes. (See 78 FR 76444 for further
discussion of the term ``antimicrobial soaps.'') In contrast, in the
1994 TFM, we proposed that both consumer antiseptic hand washes and
health care personnel hand washes should have the same effectiveness
testing and performance criteria. In response to the 1994 TFM, we
received submissions from the public arguing that consumer products
serve a different purpose and should continue to be distinct from
health care antiseptics. We agree, and in this proposed rule, we make a
distinction between consumer antiseptics for use by the general
population and health care antiseptics for use in hospitals or in other
specific health care situations outside the hospital.
    The health care setting is different from the consumer setting in
many ways. Among other things, health care facilities employ frequent,
standardized disinfection procedures and stringent infection control
measures that include the use of health care antiseptics. The use of
these measures is critical to preventing the spread of infection within
health care facilities. The population in a hospital or health care
facility also is different from the general consumer population. In
addition, the microorganisms of concern are different in the health
care and consumer settings. These differences have resulted in our
proposing different effectiveness data requirements. (See section VI.B.
about the different effectiveness data requirements.)

C. This Proposed Rule Covers Only Health Care Antiseptics

    We refer to the group of products covered by this proposed rule as
``health care antiseptics.'' In this proposed rule, FDA proposes the
establishment of a monograph for 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, but that are not
identified as ``first aid antiseptics'' in the 1991 First Aid TFM. In
this proposed 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 preoperative skin preparations
    This proposed rule covers products that are rubs and others that
are washes. The 1994 TFM did not distinguish between products that we
are now calling ``antiseptic washes'' and products we are now calling
``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 preoperative skin preparations.
    The 1994 TFM did not distinguish between consumer antiseptic washes
and rubs, and health care hand washes and rubs. This proposed rule
covers health care personnel hand washes and health care personnel hand
rubs, as well as the other health care antiseptic categories previously
listed in this section. This proposed rule does not cover consumer
antiseptic washes or consumer antiseptic hand rubs.
    Completion of the monograph for Health Care Antiseptic Products and
certain other monographs for the active ingredient triclosan are
subject to a Consent Decree entered by the United States 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.).

D. Comment Period

    Because of the complexity of this proposed rule, we are providing a
comment period of 180 days. Moreover, new data or information may be
submitted to the docket via http://www.regulations.gov within 12 months
of publication, and comments on any new data or information may then be
submitted for an additional 60 days (see Sec.  330.10(a)(7)(iii) and
(a)(7)(iv)). In addition, FDA will also consider requests to defer
further rulemaking with respect to a specific active ingredient to
allow the submission of new safety or effectiveness data to the record
if such requests are submitted to the docket within the initial 180-day
comment period. Upon the close of the comment period, FDA will review
all data and information submitted to the record in conjunction with
all timely and complete requests to defer rulemaking. In assessing
whether to defer further rulemaking for a particular active ingredient
to allow for additional time for studies to generate new data and
information, FDA will consider the data already in the docket along
with any information that is provided in any requests. FDA will
determine whether the sum of the data, if submitted in a timely
fashion, is likely to be adequate to provide all the data that are
necessary to make a determination of general recognition of safety and
effectiveness.
    We note that the OTC Drug Review is a public process and any data
submitted is public. There is no requirement or expectation that more
than one set of data will be submitted to the docket for a particular
active ingredient, and it does not matter who submits the data.
Additionally, data and other information for a single active ingredient
may be submitted by any interested party and not all data for an
ingredient must be submitted by a single party.

II. Background

    In this section, we describe the significant rulemakings and public
meetings relevant to this proposed rule, and how we are responding to
comments received in response to the 1994 TFM.

A. Significant Rulemakings Relevant to This Proposed Rule

    A summary of the significant Federal Register publications relevant
to this proposed rule is provided in table 1. Other Federal Register
publications relevant to this proposed rule are available from the
Division of Dockets Management (see ADDRESSES).

   Table 1--Significant Rulemaking Publications Related to Health Care
                        Antiseptic Drug Products
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      Federal Register notice               Information in notice
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1974 ANPR (September 13, 1974, 39   We published an advance notice of
 FR 33103).                          proposed rulemaking to establish a
                                     monograph for OTC topical
                                     antimicrobial drug products,
                                     together with the recommendations
                                     of the Advisory Review Panel on OTC
                                     Topical Antimicrobial I Drug
                                     Products (Antimicrobial I Panel or
                                     Panel), which was the advisory
                                     review 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. The 1978 TFM reflects our
                                     evaluation of the recommendations
                                     of the Panel and comments and data
                                     submitted in response to the
                                     Panel's recommendations.
1982 Alcohol ANPR (May 21, 1982,    We published an advance notice of
 47 FR 22324).                       proposed rulemaking to establish a
                                     monograph for alcohol drug products
                                     for topical antimicrobial use,
                                     together with the recommendations
                                     of the Advisory Review Panel on OTC
                                     Miscellaneous External Drug
                                     Products, which was the advisory
                                     review panel responsible for
                                     evaluating data on the active
                                     ingredients in this drug class
                                     (Miscellaneous External Panel).
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 First Aid TFM, we proposed
                                     that first aid antiseptic drug
                                     products be indicated for the
                                     prevention of skin infections in
                                     minor cuts, scrapes, and burns.
1994 Health-Care Antiseptic TFM     We amended the 1978 TFM to establish
 (June 17, 1994, 59 FR 31402).       a separate monograph for the group
                                     of products that were referred to
                                     as OTC topical health care
                                     antiseptic drug products. These
                                     antiseptics are generally intended
                                     for use by health care
                                     professionals.
                                    In that proposed rule, 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 that proposed rule, we proposed
                                     that additional safety and
                                     effectiveness data are necessary to
                                     support the safety and
                                     effectiveness of consumer
                                     antiseptic wash active ingredients.
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B. Public Meetings Relevant to This Proposed Rule

    In addition to the Federal Register publications listed in table 1,
there have been three meetings of the NDAC and one public feedback
meeting 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
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     Date and type of meeting                Topic of discussion
------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint    Antiseptic and antibiotic resistance
 meeting with the Anti-Infective     in relation to an industry proposal
 Drugs Advisory Committee)           for consumer and health care
 (January 6, 1997, 62 FR 764).       antiseptic effectiveness testing
                                     (Health Care Continuum Model)
                                     (Refs. 6 and 7).
March 2005 NDAC Meeting (February   The use of surrogate endpoints and
 18, 2005, 70 FR 8376).              study design issues for the in vivo
                                     testing of health care antiseptics
                                     (Ref. 8).
November 2008 Public Feedback       Demonstration of the effectiveness
 Meeting.                            of consumer antiseptics (Ref. 9).
September 2014 NDAC Meeting (July   Safety testing framework for health
 29, 2014, 79 FR 44042).             care antiseptic active ingredients
                                     (Ref. 10).
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C. Comments Received by FDA

    In response to the 1994 TFM, FDA received approximately 160
comments from drug manufacturers, trade associations, academia, testing
laboratories, consumers, health professionals, and law firms. Copies of
the comments received are on public display at http://www.regulations.gov (see ADDRESSES).
    Because only health care antiseptics are discussed in this proposed
rule, only those comments and data received in response to the 1994 TFM
that are related to health care antiseptic active ingredients are
addressed. We also received comments related to final formulation
testing and labeling conditions proposed in the 1994 TFM. If in the
future we determine that there are monograph health care antiseptic
active ingredients that are GRAS/GRAE, we will address these comments.
We invite further comment on the final formulation testing and labeling
conditions proposed in the 1994 TFM, particularly in light of the
conditions proposed in this proposed rule. Comments that were received
in response to the 1994 TFM regarding other intended uses of the active
ingredients are addressed in the Consumer Antiseptic Wash TFM (78 FR
76444), or will be addressed in future documents related to those other
uses.
    This proposed rule constitutes FDA's evaluation of submissions made
in response to the 1994 TFM to support the safety and effectiveness of
OTC health care antiseptic active ingredients (Refs. 11 and 12). We
reviewed the available literature and data and other comments submitted
to the rulemaking and are proposing that adequate data for a
determination of safety and effectiveness are not yet available for the
health care antiseptic active ingredients.

III. Active Ingredients With Insufficient Evidence of Eligibility for
the OTC Drug Review

    In this section of the proposed rule, we describe the requirements
for

eligibility for the OTC Drug Review and the ingredients submitted to
the OTC Drug Review that lack adequate evidence of eligibility for
evaluation as health care antiseptic products.

A. Eligibility for the OTC Drug Review

    An OTC drug is covered by the OTC Drug Review if its conditions of
use existed in the OTC drug marketplace on or before May 11, 1972 (37
FR 9464).\1\ Conditions of use include, among other things, active
ingredient, dosage form and strength, route of administration, and
specific OTC use or indication of the product (see 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 prior to 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 will require FDA
approval through the NDA process. Ineligibility for use as a specific
type of health care antiseptic (e.g., health care personnel hand wash
or surgical hand scrub) does not affect eligibility for other
indications under the health care antiseptic monograph (e.g., patient
preoperative skin preparations) or under any other OTC drug monograph.
---------------------------------------------------------------------------

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

    Section III.B discusses those ingredients that currently do not
have adequate evidence of eligibility for evaluation under the OTC Drug
Review based on a review of the labeling submitted to the Panel. Some
ingredients are ineligible for any of the categories of health care
antiseptics. Others are eligible for some, but not others. Because of
their lack of eligibility, effectiveness and safety information that
has been submitted to the rulemaking for these health care antiseptic
active ingredients are not discussed in this proposed rule for such
use(s). However, if documentation of the type described in this section
is submitted, these active ingredients could be determined to be
eligible for evaluation for such use(s).

B. Eligibility of Certain Active Ingredients for Certain Health Care
Antiseptic Uses Under the OTC Drug Review

    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 each of the five health care
antiseptic uses: Patient preoperative skin preparation, health care
personnel hand wash, health care personnel hand rub, surgical hand
scrub, and surgical hand rub. After the table, we discuss the
ineligibility of ingredients in this section of the proposed rule.

            Table 3--Eligibility of Antiseptic Active Ingredients for Health Care Antiseptic Uses \1\
----------------------------------------------------------------------------------------------------------------
                                                   Patient
                                                preoperative  Health care  Health care    Surgical     Surgical
               Active ingredient                    skin       personnel    personnel    hand scrub    hand rub
                                                 preparation   hand wash     hand rub
----------------------------------------------------------------------------------------------------------------
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 Active Ingredients:
    Iodine complex (ammonium ether sulfate and             N            Y            N            Y            N
     polyoxyethylene sorbitan monolaurate)....
    Iodine complex (phosphate ester of                     Y            Y            N            Y            N
     alkylaryloxy polyethylene glycol)........
    Iodine tincture USP.......................             Y            N            N            N            N
    Iodine topical solution USP...............             Y            N            N            N            N
    Nonylphenoxypoly (ethyleneoxy)                         Y            Y            N            Y            N
     ethanoliodine............................
    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 (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,                        Y            N            N            N            N
     triethanolamine, and phenol derivative...
    Mercufenol chloride and secondary                      Y            N            N            N            N
     amyltricresols 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).
\2\ Y = Eligible for specified use.
\3\ N = Ineligible for specified use.

1. Alcohols
    a. Alcohol (ethanol or ethyl alcohol). In the 1994 TFM, alcohol
(ethanol or ethyl alcohol) 60 to 95 percent by volume in an aqueous
solution was evaluated for use as a health care personnel hand wash,
surgical hand scrub, and patient preoperative skin preparation (59 FR
31402 at 31442). The only health care antiseptic products containing
alcohol that were submitted to the OTC Drug Review were products that
were intended to be used without water (i.e., rubs and skin
preparations) (Ref. 13). Consequently, based on the information we
currently have about eligibility, we propose to categorize as new drugs
these health care antiseptic washes and surgical scrubs (both of which
are washes and are by definition intended to be rinsed off with water)
that contain alcohol as the active ingredient, and we do not include a
discussion of safety or effectiveness of alcohol for such rinse-off
uses in this proposed rule.
    Alcohol, however, has been demonstrated to be eligible for the OTC
Drug Review for use as a health care personnel hand rub, surgical hand
rub, and patient preoperative skin preparation (59 FR 31402 at 31435-
31436). Thus, we include a discussion of the safety and effectiveness
data for alcohol in this proposed rule for such uses.
    b. Isopropyl alcohol. In the 1994 TFM, isopropyl alcohol 70 to 91.3
percent by volume in an aqueous solution (isopropyl alcohol) was
classified for use as a health care personnel hand wash and surgical
hand scrub (59 FR 31402 at 31435-31436). Isopropyl alcohol also was
evaluated as a patient preoperative skin preparation (59 FR 31402 at
31442-31443). The only health care antiseptic products containing
isopropyl alcohol that were submitted to the OTC Drug Review were
products that were intended to be used without water (i.e., rubs and
skin preparations) (Ref. 13). Consequently, isopropyl alcohol has not
been demonstrated to be eligible for the OTC Drug Review for use as a
health care personnel hand wash or a surgical hand scrub drug product,
both of which are washes and by definition are intended to be rinsed
off with water. Thus, we propose to categorize isopropyl alcohol for
these uses as a new drug and do not include a discussion of safety or
effectiveness of isopropyl alcohol for such rinse-off uses in this
proposed rule.
    Isopropyl alcohol, however, has been demonstrated to be eligible
for the OTC Drug Review for use as a health care personnel hand rub,
surgical hand rub, and patient preoperative skin preparation (59 FR
31402 at 31435-31436). Thus, we include a discussion of the safety and
effectiveness data for isopropyl alcohol in this proposed rule for such
uses.
2. Benzalkonium Chloride
    Benzalkonium chloride has not been demonstrated to be eligible for
the OTC Drug Review for use as a surgical hand rub. Based on the
information we currently have about eligibility, we propose to
categorize as a new drug benzalkonium chloride for use as a surgical
hand rub. Benzalkonium chloride, however, has been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash, health care personnel hand rub, surgical hand scrub, and
patient preoperative skin preparation (59 FR 31402 at 31435-31436).
Thus, we include a discussion of the safety and effectiveness data for
benzalkonium chloride in this proposed rule for such uses.
3. Chlorhexidine Gluconate
    Previously, chlorhexidine gluconate 4 percent aqueous solution
(chlorhexidine gluconate) was found to be ineligible for inclusion in
the monograph for any health care antiseptic use and was not included
in the 1994 TFM (59 FR 31402 at 31413). We have not received any new
information since the 1994 TFM demonstrating that this active
ingredient is eligible for the monograph. Consequently, we are not
proposing to change the categorization of chlorhexidine gluconate from
that of a new drug based on the lack of documentation demonstrating its
eligibility as a health care antiseptic, and we do not include a
discussion of any safety or effectiveness data submitted for
chlorhexidine gluconate in this proposed rule.
4. Iodine and Iodine Complexes
    a. Iodine topical solution USP and iodine tincture USP. Iodine
topical solution and iodine tincture have not been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash or rub or as a surgical hand scrub or rub. Neither iodine
topical solution nor iodine tincture was evaluated for these uses in
the1994 TFM (59 FR 31402 at 31435-31436), and we have not received any
new information to demonstrate eligibility for these uses since
publication of the 1994 TFM. Based on the information we currently have
about eligibility of iodine topical solution and iodine tincture, we
propose to categorize as new drugs these iodines intended for use as a
health care personnel hand wash or rub or as a surgical hand scrub or
rub, and we do not include a discussion of safety or effectiveness of
iodine solution or tincture for such uses in this proposed rule.
    However, both iodine topical solution and iodine tincture have been
demonstrated to be eligible for the OTC Drug Review for use as a
patient preoperative skin preparation (59 FR 31402 at 31435-31436).
Thus, we include a discussion of the safety and effectiveness of these
iodines for this use in this proposed rule.
    b. Iodine complex (ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate). The only health care antiseptic products
containing this iodine complex submitted to the OTC Drug Review were
health care personnel hand washes and surgical hand scrubs intended to
be used with water (Ref. 13). Consequently, iodine complex (ammonium
ether sulfate and polyoxyethylene sorbitan monolaurate) has not been
demonstrated to be eligible for the OTC Drug Review for evaluation as a
health care personnel hand rub or a surgical hand rub, both of which
are intended to be leave-on products used without water. This iodine
complex also has not been demonstrated to be eligible for the OTC Drug
Review for use as a patient preoperative skin preparation. It was not
evaluated for use as a patient preoperative skin preparation in the
1994 TFM (59 FR 31402 at 31435-31436) and we have not received any new
information to demonstrate eligibility for this use since publication
of the 1994 TFM. Based on the information we currently have about
eligibility of this active ingredient, we propose to categorize as a
new drug iodine complex (ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate) intended for use as patient preoperative skin
preparation as well. This iodine complex, however, has been
demonstrated to be eligible for the OTC Drug Review for use as a health
care personnel hand wash and surgical hand scrub (59 FR 31402 at 31435-
31436).
    c. Iodine complex (phosphate ester of alkylaryloxy polyethylene
glycol), nonylphenoxypoly (ethyleneoxy) ethanoliodine, poloxamer-iodine
complex, and undecoylium chloride iodine complex. The only health care
antiseptic products containing these iodine complexes that were
submitted to the OTC Drug Review were health care personnel hand washes
and surgical hand scrubs intended to be used with water, and patient
preoperative skin preparations (Ref. 13). Consequently, iodine complex

(phosphate ester of alkylaryloxy polyethylene glycol), nonylphenoxypoly
(ethyleneoxy) ethanoliodine, poloxamer-iodine complex, and undecoylium
chloride iodine complex have not been demonstrated to be eligible for
the OTC Drug Review for evaluation as health care personnel hand rubs
or surgical hand rubs (59 FR 31402 at 31418 and 31435-31436). Thus, we
do not include a discussion of safety or effectiveness of these iodine
complexes for these uses in this proposed rule.
    These active ingredients, however, have been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash, a surgical hand scrub, and a patient preoperative skin
preparation (59 FR 31402 at 31435-31436). Thus, we include a discussion
of the safety and effectiveness of these ingredients for these uses in
this proposed rule.
    d. Povidone-iodine 5 to 10 percent. The only health care antiseptic
products containing povidone-iodine 5 to 10 percent submitted to the
OTC Drug Review were health care personnel hand washes and surgical
hand scrubs intended to be used with water (Ref. 13). Povidone-iodine 5
to 10 percent has not been demonstrated to be eligible for the OTC Drug
Review for evaluation as a health care personnel hand rub or surgical
hand rub, and we propose to categorize povidone-iodine for these uses
as a new drug. However, povidone-iodine has been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash, surgical hand scrub, and patient preoperative skin
preparation (59 FR 31402 at 31423 and 31435-31436). Thus, we include a
discussion of the safety and effectiveness of povidone iodine for these
uses in this proposed rule.
5. Mercufenol Chloride
    Mercufenol chloride was evaluated for use only as a patient
preoperative skin preparation in the 1994 TFM (59 FR 31402 at 31428-
31429 and 31435-31436). Based on the information we currently have
about eligibility, we propose to categorize as a new drug mercufenol
chloride for use as a health care personnel hand wash or rub or as a
surgical hand scrub or rub. Mercufenol chloride, however, has been
demonstrated to be eligible for the OTC Drug Review for use as a
patient preoperative skin preparation.
6. Polyhexamethylene Biguanide; Benzalkonium Cetyl Phosphate;
Cetylpyridinium Chloride; Salicylic Acid; Sodium Hypochlorite; Tea Tree
Oil; Combination of Potassium Vegetable Oil Solution, Phosphate
Sequestering Agent, and Triethanolamine
    Following the publication of the 1994 TFM, FDA received submissions
for the first time requesting that polyhexamethylene biguanide;
benzalkonium cetyl phosphate; cetylpyridinium chloride; salicylic acid;
sodium hypochlorite; tea tree oil; and the combination of potassium
vegetable oil solution, phosphate sequestering agent, and
triethanolamine be added to the monograph (Refs. 14 through 19). These
compounds were not addressed in prior FDA documents related to the
monograph and were not evaluated for any health care antiseptic use by
the Antimicrobial I Panel. The submissions received by FDA to date do
not include documentation demonstrating the eligibility of any of these
seven compounds for inclusion in the monograph (Ref. 20). Therefore,
polyhexamethylene biguanide, benzalkonium cetyl phosphate,
cetylpyridinium chloride, salicylic acid, sodium hypochlorite, tea tree
oil, and the combination of potassium vegetable oil solution, phosphate
sequestering agent, and triethanolamine have not been demonstrated to
be eligible for the OTC Drug Review. Based on the information we
currently have about eligibility, we propose to categorize these
compounds as new drugs and we do not include a discussion of safety or
effectiveness data submitted for them in this proposed rule.
7. Other Individual Active Ingredients
    In the 1994 TFM, each of the following ingredients was evaluated
for use as a patient preoperative skin preparation, a health care
personnel hand wash, and a surgical hand scrub (59 FR 31402 at 31435-
31436):

 Benzethonium chloride
 Chloroxylenol
 Cloflucarban
 Fluorosalan
 Hexylresorcinol
 Methylbenzethonium chloride
 Phenol (less than 1.5 percent)
 Secondary amyltricresols
 Sodium oxychlorosene
 Triclocarban
 Triclosan

    The only health care personnel hand wash or surgical hand scrub
products containing any of these ingredients that were submitted to the
OTC Drug Review were products that were intended to be used with water
(i.e., rinse-off products) (Ref. 13). Consequently, based on the
information we currently have about eligibility, we propose to
categorize as a new drug each of these ingredients for use as a health
care personnel hand rub or a surgical hand rub, and we do not include a
discussion of safety or effectiveness of these ingredients for these
uses in this proposed rule.
    Each of the listed ingredients, however, has been demonstrated to
be eligible for the OTC Drug Review for use as a health care personnel
hand wash, surgical hand scrub, and patient preoperative skin
preparation.
8. Combination Active Ingredients
    The combination active ingredients (1) calomel, oxyquinoline
benzoate, triethanolamine, and phenol derivative; (2) mercufenol
chloride and secondary amyltricresols in 50 percent alcohol; and (3)
triple dye have not been demonstrated to be eligible for the OTC Drug
Review for use as a health care personnel hand wash or rub or as a
surgical hand scrub or rub (59 FR 31402 at 31435-31436). Consequently,
based on the information we currently have about eligibility, we
propose to categorize as a new drug each of these ingredients for use
as a health care personnel hand wash, health care personnel hand rub,
surgical hand scrub, or a surgical hand rub, and we do not include a
discussion of safety or effectiveness of these ingredients for these
uses in this proposed rule. However, each of the previously discussed
active ingredients has been demonstrated to be eligible for the OTC
Drug Review for use as a patient preoperative skin preparation.

IV. 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 31435-31436), FDA proposed that the active ingredients
fluorosalan, hexachlorophene, phenol (greater than 1.5 percent), and
tribromsalan be found not GRAS/GRAE for the uses referred to in the
1994 TFM as antiseptic hand wash and health care personnel hand wash.
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 to support
reclassification of any of these ingredients to GRAS/GRAE status.
Therefore, FDA is continuing to propose that these active ingredients
be found not GRAS/GRAE for OTC health care antiseptic products as
defined in this proposed rule and that any OTC health care antiseptic
drug product containing any of these ingredients not be allowed to be
introduced or delivered for introduction into interstate commerce
unless it is the subject of an approved application, effective, except
as otherwise provided in other regulations, as of 1 year after
publication of the final monograph in the Federal Register.

V. Summary of Proposed Classifications of OTC Health Care Antiseptic
Active Ingredients

    Tables 4 through 7 in this proposed rule list the classification
proposed in the 1994 TFM for each OTC health care antiseptic active
ingredient according to intended use and the classification being
proposed in this proposed rule. The specific data that has been
submitted to the public docket (the rulemaking) and evaluated by FDA
and the description of data still lacking in the administrative record
is later described in detail for each active ingredient for which we
have some data in section VII.D.
    Tables 4 and 5 list ingredients for which a different status is
being proposed in this proposed rule than was proposed in the 1994 TFM.

   Table 4--Classification of OTC Health Care Personnel Hand Wash and
 Surgical Hand Scrub Antiseptic Active Ingredients in This Proposed Rule
                           and in the 1994 TFM
------------------------------------------------------------------------
                                                         This proposed
         Active ingredient               1994 TFM             rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent..........  I \1\              IIISE \2\
Hexylresorcinol...................  IIIE               IIISE
Iodine complex (ammonium ether      IIIE               IIISE
 sulfate and polyoxyethylene
 sorbitan monolaurate).
Iodine complex (phosphate ester of  IIIE               IIISE
 alkylaryloxy polyethylene glycol).
Isopropyl alcohol 70 to 91.3        IIIE               IIISE
 percent.
Nonylphenoxypoly (ethyleneoxy)      IIIE               IIISE
 ethanoliodine.
Poloxamer iodine complex..........  IIIE               IIISE
Povidone-iodine 5 to 10 percent...  I                  IIISE
Secondary amyltricresols..........  IIIE               IIISE
Triclocarban......................  IIIE               IIISE
Undecoylium chloride iodine         IIIE               IIISE
 complex.
------------------------------------------------------------------------
\1\ ``I'' denotes a classification that an active ingredient has been
  shown to be safe and effective.
\2\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.

  Table 5--Classification of OTC Patient Preoperative Skin Preparation
 Antiseptic Active Ingredients in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
                                                         This proposed
         Active ingredient               1994 TFM             rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent..........  I \1\              IIISE \2\
Benzalkonium chloride.............  IIIE               IIISE
Benzethonium chloride.............  IIIE               IIISE
Chloroxylenol.....................  IIIE               IIISE
Hexylresorcinol...................  IIIE               IIISE
Iodine complex (phosphate ester of  IIIE               IIISE
 alkylaryloxy polyethylene glycol).
Iodine tincture USP...............  I                  IIISE
Iodine topical solution USP.......  I                  IIISE
Isopropyl alcohol 70 to 91.3        I                  IIISE
 percent.
Mercufenol chloride...............  IIIE               IIISE
Methylbenzethonium chloride.......  IIIE               IIISE
Nonylphenoxypoly (ethyleneoxy)      IIIE               IIISE
 ethanoliodine.
Phenol (less than 1.5 percent)....  IIIE               IIISE
Poloxamer iodine complex..........  IIIE               IIISE
Povidone-iodine 5 to 10 percent...  I                  IIISE
Triclocarban......................  IIIE               IIISE
Triclosan.........................  IIIE               IIISE
Undecoylium chloride iodine         IIIE               IIISE
 complex.
------------------------------------------------------------------------
\1\ ``I'' denotes a classification that an active ingredient has been
  shown to be safe and effective.
\2\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.

    This proposed rule does not change the status of a number of
antiseptic active ingredients previously proposed as lacking sufficient
evidence of safety or effectiveness or the status of several
ingredients previously proposed as having been shown to be unsafe,
ineffective, or both (see tables 6 and 7).

  Table 6--OTC Health Care Personnel Hand Wash and Surgical Hand Scrub
 Antiseptic Active Ingredients With No Change in Classification in This
                 Proposed Rule Compared to the 1994 TFM
------------------------------------------------------------------------
             Active ingredient               No change in classification
------------------------------------------------------------------------
Benzalkonium chloride.....................  IIISE \1\
Benzethonium chloride.....................  IIISE
Chloroxylenol.............................  IIISE
Cloflucarban..............................  IIISE/II \2\
Fluorosalan...............................  II \3\
Hexachlorophene...........................  II
Methylbenzethonium chloride...............  IIISE
Phenol (less than 1.5 percent)............  IIISE
Phenol (greater than 1.5 percent).........  II
Sodium oxychlorosene......................  IIISE
Tribromsalan..............................  II
Triclosan.................................  IIISE
------------------------------------------------------------------------
\1\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.
\2\ Health care personnel hand wash proposed as IIISE and surgical hand
  scrub proposed as II.
\3\ ``II'' denotes a classification that an active ingredient has been
  shown to be unsafe, ineffective, or both.

  Table 7--OTC Patient Preoperative Skin Preparation Antiseptic Active
   Ingredients With No Change in Classification in This Proposed Rule
                        Compared to the 1994 TFM
------------------------------------------------------------------------
             Active ingredient               No change in classification
------------------------------------------------------------------------
Cloflucarban..............................  II \1\
Fluorosalan...............................  II
Hexachlorophene...........................  II
Phenol (greater than 1.5 percent).........  II
Secondary amyltricresols..................  IIISE \2\
Sodium oxychlorosene......................  IIISE
Tribromsalan..............................  II
Calomel, oxyquinoline benzoate,             II
 triethanolamine, and phenol derivative.
Mercufenol chloride and secondary           IIISE
 amyltricresols in 50 percent alcohol.
Triple dye................................  II
------------------------------------------------------------------------
\1\ ``II'' denotes that an active ingredient has been shown to be
  unsafe, ineffective, or both.
\2\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.

VI. Effectiveness (Generally Recognized as Effective) Determination

    OTC regulations (Sec. Sec.  330.10(a)(4)(ii) and 314.126(b)) define
the standards for establishing that an OTC drug containing a particular
active ingredient would be GRAE for its intended use. These regulations
provide that supporting investigations must be adequate and well-
controlled, and able to distinguish the effect of a drug from other
influences such as a spontaneous change in the course of the disease,
placebo effect, or biased observation. In general, such investigations
include controls that are adequate to provide an assessment of drug
effect, are adequate measures to minimize bias, and use adequate
analytical methods to demonstrate effectiveness. For active ingredients
being evaluated in the OTC Drug Review, this means that a demonstration
of the contribution of the active ingredient to any effectiveness
observed is required before an ingredient can be determined to be GRAE
for OTC drug use.
    In the 1994 TFM, we proposed a log reduction standard (a clinical
simulation standard) for establishing effectiveness of consumer and
health care antiseptics (59 FR 31402 at 31448) for the proposed
intended use of decreasing bacteria on the skin. The 1994 TFM log
reduction standard for effectiveness is based on a surrogate endpoint
(i.e., number of bacteria removed from the skin), rather than a
clinical outcome (e.g., reduction in the number of infections). In
accordance with recommendations made by NDAC at its March 2005 meeting,
we continue to propose a log reduction standard to demonstrate the
general recognition of effectiveness of health care antiseptic active
ingredients. See section VI.B for our current proposed log reduction
standard.
    Unlike the use of antiseptics in the consumer setting, the use of
antiseptics by health care providers in the hospital setting is
considered an essential component of hospital infection control
measures (Refs. 21, 22, and 23). Hospital-acquired infections can
result in prolonged hospital stays, additional medical treatment,
adverse clinical outcomes, and increased health care costs (Refs. 24
through 27). The reliance on antiseptics in the clinical setting goes
back over 150 years when, in the mid-1800s, Semmelweis observed that
the mortality associated with childbed fever at the General Hospital in
Vienna could be reduced by disinfection of physicians' hands with
chlorine prior to patient care (Ref. 28). Around the same time, Lister
demonstrated the effect of skin disinfection on surgical site infection
rates (Ref. 28). This observational evidence of the effect of
antiseptics on infection by Semmelweis and Lister form the basis for
the current role of antiseptics as a critical component of hospital
infection control procedures. Adequate and well-controlled clinical
trials demonstrating a definitive link between antiseptic use and a
reduction in infection rates are lacking, however.
    The March 2005 NDAC acknowledged the difficulty in designing
clinical trials to demonstrate the impact of health care antiseptics on
infection rates. This difficulty was one reason the committee advised
against clinical outcome trials to demonstrate the effectiveness of
health care antiseptics. Numerous factors contribute to hospital-
acquired infections and, therefore, would need to be controlled for in
the design of these types of studies. For example, some of the known
risk factors for surgical site infection that must be controlled for
include the following: Patient age, nutritional status, diabetes,
smoking, obesity, coexistent infections at a remote body site,
colonization with microorganisms, altered immune response, length of
preoperative stay, duration of surgical scrub, preoperative shaving,
preoperative skin prep, duration of the operation, inadequate
sterilization of instruments, foreign material in the surgical site,
surgical drain, and surgical technique (Ref. 22). There are also
standard infection control measures such as gloving, isolation
procedures, sterilization of instruments, and waste disposal that make
it difficult to demonstrate the independent contribution of antiseptics
to the reduction of the risk of hospital infection (Ref. 28).
    Although we found a few studies that could serve as a basis for
designing a clinical outcome study in the consumer setting (78 FR 76444
at 76450), we have not found any acceptable clinical outcome study
designs for health care antiseptics. The March 2005 NDAC recommended
that sponsors 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. We have not seen any
studies of this type. The March 2005 NDAC also believed that it would
be unethical to perform a hospital trial using a vehicle control
instead of an antiseptic. Although the NDAC thought

that performing a placebo-controlled study for routine patients on the
ward might be feasible, it stated that the Centers for Disease Control
and Prevention hand hygiene guidelines and hospital accreditation
requirements would prohibit such a practice. The NDAC also believed
that an institutional review board would not approve a hospital trial
that did not involve an antiseptic.
    We agree that a clinical outcome study in the health care setting
raises ethical concerns. For a clinical outcome study to be adequately
controlled the study design would need to include a vehicle or negative
control arm. However, 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 a
nonantimicrobial product 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. Thus, it
is generally considered unethical to perform placebo-controlled
clinical studies to show the value of health care antiseptics (Ref. 8).
Based on these considerations NDAC recommended the continued use of
clinical simulation studies to validate the effectiveness of health
care antiseptics.
    FDA has relied upon clinical simulation studies to support the
approval of health care antiseptics through the NDA process. Although
it is not possible to quantify the contribution of NDA health care
antiseptics to reduced hospital infection rates, in general, infection
rates in the United States are low. For example, only 2 to 5 percent of
over 40 million inpatient surgical procedures each year are complicated
by surgical site infections (Ref. 29). We acknowledge that the use of
surrogate endpoints to assess the effectiveness of these products is
not optimal, but we believe it is the best means available of assessing
the effectiveness of health care antiseptic products.
    Thus, we are continuing to rely on surrogate endpoints to evaluate
the effectiveness of health care antiseptics while requiring data from
clinical outcome studies to support the effectiveness of consumer
antiseptics (78 FR 76444 at 76450). Unlike consumer antiseptics,
however, health care antiseptics are considered an integral part of
hospital infection control strategies (Refs. 21, 23, and 30). As is the
case for consumer antiseptics, we lack clinical outcome data from
adequate studies demonstrating the impact of health care antiseptics on
infection rates. Given this, FDA faces the challenge of regulating this
important component of current hospital infection control measures
without methods to directly assess their clinical effect. We
nonetheless need a practical means to assess the general recognition of
effectiveness of health care products, such as the clinical simulation
studies.
    As discussed in section VI.A, we evaluated all the available
effectiveness studies for health care antiseptics (i.e., health care
personnel hand washes and rubs, surgical hand scrubs and rubs, and
patient preoperative skin preparations) to determine whether the data
supported finding the health care antiseptic active ingredient to be
GRAE based on the 1994 TFM effectiveness criteria (which we are now
proposing to update). We found that the available studies are not
adequate to support a GRAE determination for any health care antiseptic
active ingredient under the 1994 TFM effectiveness criteria (59 FR
31402 at 31445, 31448, and 31450).\2\
---------------------------------------------------------------------------

    \2\ We note that alcohol, isopropyl alcohol, and some iodine-
containing active ingredients were proposed as GRAE in the 1994 TFM;
however, the studies that supported that proposal do not meet our
current standards for adequate and well-controlled studies. See
discussion in section VI.A.1.
---------------------------------------------------------------------------

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
    Most of the data available to support the effectiveness of health
care antiseptics are based on clinical simulation studies, such as the
ones described in the 1994 TFM (59 FR 31402 at 31444). In vivo test
methods, such as clinical simulation studies, and evaluation criteria
proposed in the 1994 TFM 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 conditions of such
use. For example, one of the intended purposes of a health care
personnel hand wash is to reduce the risk of patient-to-patient cross
contamination. Thus, the clinical simulation studies proposed in the
1994 TFM are designed to demonstrate effectiveness of a product in the
presence of repeated bacterial challenge. The hands are artificially
contaminated with a marker organism (bacteria), and the reduction from
the baseline numbers of the contaminating organism is determined after
use of the test product. This contamination and hand wash procedure is
repeated several times, and bacterial reductions are measured at
various time points. This aspect of the study design is intended to
mimic the repeated use of the product (59 FR 31402 at 31448).
    The testing proposed in the 1994 TFM for surgical hand scrubs and
patient preoperative skin preparations involves testing against
resident skin microflora (bacteria that normally colonize the skin),
and there is no artificial contamination of the skin in these studies.
Testing demonstrates that the resident bacterial load is highly
variable among individuals within the general population (Refs. 31 and
32). Although the 1994 TFM methods specify a minimum bacterial count
for individuals to be included in the assessment of surgical hand
scrubs and patient preoperative skin preparations, there can be
considerable intersubject variability. Similar to the health care
personnel hand washes, the testing of a surgical hand scrub proposed in
the 1994 TFM involves multiple test product uses and the repeated
measurement of bacterial reductions to determine both immediate and
persistent antimicrobial activity (59 FR 31402 at 31445). The patient
preoperative skin preparation test evaluates a single application of
the product on a dry skin site (abdomen or back) and a moist skin site
(groin or axilla) with higher numbers of resident bacteria (59 FR 31402
at 31450). The effectiveness criteria for patient preoperative skin
preparations and surgical hand scrubs proposed in the 1994 TFM also
require that bacterial growth be suppressed for 6 hours (59 FR 31402 at
31445 and 31450).
    We evaluated all clinical simulation studies that were submitted to
the OTC Drug Review for evidence of health care personnel hand
antiseptic, surgical hand antiseptic, and patient preoperative skin
preparation effectiveness demonstrated under the log reduction criteria
proposed in the 1994 TFM (59 FR 31402 at 31445, 31448, and 31450) (Ref.
33). We also searched the published literature for clinical simulation
studies that assess health care personnel hand antiseptic, surgical
hand antiseptic, and patient preoperative skin preparation
effectiveness using the log reduction criteria in the 1994 TFM (Refs.
33 through 36).
    Overall, the studies used a variety of study designs, including
nonstandard study designs. In some cases, such as for surgical hand
antiseptics, data submitted to the OTC Drug Review was

in the form of abstracts and technical reports. There is insufficient
information to evaluate the scientific merit of studies described in
abstracts and technical reports. Most importantly, none of the
evaluated studies were adequately controlled to demonstrate the
contribution of the active ingredient to the effectiveness observed in
the studies (43 FR 1210 at 1240) and, therefore, cannot be used to
demonstrate that the active ingredient tested is GRAE.
    In general, the evaluated studies also had other deficiencies. Each
study had at least one of the following deficiencies:
     Some studies that were described as using a standardized
method (American Society for Testing and Materials (ASTM) or 1994 TFM)
varied from these methods without explanation or validation, and the
majority of studies did not provide sufficient information about
critical aspects of the study conduct.
     Many studies did not include appropriate controls; for
example, some studies did not include a vehicle control or an active
control (59 FR 31402 at 31446, 31448, and 31450), and some studies that
included an active control failed to use the control product according
to its labeled directions (59 FR 31402 at 31446, 31448, and 31450).
     Many studies did not provide sufficient detail concerning
neutralizer use (43 FR 1210 at 1244) or validation of neutralizer
effectiveness.
     The studies evaluated a small number of subjects (59 FR
31402 at 31446, 31449, and 31451).
     Some studies did not sample at all of the time points
specified by the test method (59 FR 31402 at 31446, 31448, and 31450).
     In the case of patient preoperative skin preparation
studies, some studies used subjects with baseline values that were too
low and other studies did not provide baseline values at all (59 FR
31402 at 31451). Many of the studies only tested one type of test site
(dry or moist), but the 1994 TFM (as well as the testing proposed here)
requires testing of both dry and moist test sites to demonstrate
effectiveness (59 FR 31402 at 31450).
    FDA's detailed evaluation of the data is filed in Docket No. FDA-
2015-N-0101, available at http://www.regulations.gov (Refs. 33 through
36).
2. Clinical Outcome Studies
    Although we are not currently proposing to require clinical outcome
studies to support a GRAE determination in this proposal, FDA has
evaluated all the clinical outcome studies that were submitted to the
OTC Drug Review to look for evidence of a clinical benefit from the use
of health care antiseptics (Ref. 33). In addition, we searched the
published literature for clinical outcome studies that would provide
evidence of a clinical benefit from the use of a health care antiseptic
(Ref. 37). Most of these studies were designed to evaluate health care
worker compliance with hand hygiene protocols, and thus, were not
adequately controlled to demonstrate a reduction of infection rates.
Most importantly, none of the studies used a vehicle control. In
general, the studies had additional design flaws such as the following:
     A small sample size.
     A lack of randomization, blinding, or both.
     Inadequate statistical power and, in some cases, a failure
to analyze results for statistical significance.
     Inadequate description of methodology and data collection
methods.
     Inadequate documentation of proper training in hand wash
or rub, surgical hand scrub or rub, or patient preoperative skin
preparation technique.
     Failure to observe and document hand washing technique.
     Inadequate controls to address the multifactorial nature
of surgical site infection.
     Some patients received antibiotic treatment and others did
not.
     Some studies addressed nonmonograph indications.
    As discussed in section VI, the March 2005 NDAC agreed that there
are currently no clinical trials presented that showed any clinical
benefit. The committee stated that conducting such a study in the
hospital setting would be unethical, especially considering the need to
introduce a placebo or vehicle control to show contribution of an
antiseptic drug product. This would put the subjects' health at risk.

B. Current Standards: Studies Needed To Support a Generally Recognized
as Effective Determination

    In the 1994 TFM, we proposed that the effectiveness of antiseptic
active ingredients could be supported by a combination of in vitro
studies and in vivo clinical simulation testing as described in 21 CFR
333.470 (59 FR 31402 at 31444). In vitro studies are designed to
demonstrate the product's spectrum and kinetics of antimicrobial
activity, as well as the potential for the development of resistance
associated with product use. In vivo test methods and evaluation
criteria are based on the premise that bacterial reductions can be
adequately demonstrated using tests that simulate conditions of actual
use for each OTC health care antiseptic product category and that those
reductions are reflective of bacterial reductions that would be
achieved during use. (See discussion in section B.2.) Given the
limitations of our ability to study these active ingredients in a
clinical outcome study in a health care setting, a GRAE determination
for a health care antiseptic active ingredient should be supported by
an adequate characterization of the antimicrobial activity of the
ingredient through both in vitro testing and in vivo clinical
simulation testing.
1. In Vitro Studies
    The 1994 TFM proposed that the antimicrobial activity of an active
ingredient could be demonstrated in vitro by a determination of the in
vitro spectrum of antimicrobial activity, minimum inhibitory
concentration (MIC) testing against 25 fresh clinical isolates and 25
laboratory strains, and time-kill testing against 23 laboratory strains
(59 FR 31402 at 31444). Comments received in response to the 1994 TFM
objected to the proposed in vitro testing requirements, stating that
they were overly burdensome (Ref. 38). Consequently, submissions of in
vitro data submitted to support the effectiveness of antiseptic active
ingredients were far less extensive than what was proposed in the 1994
TFM (Ref. 39). Although we agree that the in vitro testing proposed in
the 1994 TFM is overly burdensome for testing every final formulation
of an antiseptic product that contains a GRAE ingredient, we continue
to believe that a GRAE determination for a health care antiseptic
active ingredient should be supported by adequate in vitro
characterization of the antimicrobial activity of the ingredient. In
addition, we now propose the option of assessing the minimum
bactericidal concentration (MBC) as an alternative to testing the MIC
to demonstrate the broad spectrum activity of the antiseptic. The
ability of an antiseptic to kill microorganisms, rather than inhibit
them, is more relevant for a topical product. Because the determination
of GRAE status is a very broad statement that can apply to many
different formulations of an active ingredient, we continue to propose
that an evaluation of the spectrum and kinetics of antimicrobial
activity of a health care antiseptic active ingredient should include
the following:
     A determination of the in vitro spectrum of antimicrobial
activity against recently isolated normal flora

and cutaneous pathogens (59 FR 31402 at 31444).
     MIC or MBC testing of 25 representative clinical isolates
and 25 reference (e.g., American Type Culture Collection) strains of
each of the microorganisms listed in the 1994 TFM (59 FR 31402 at
31444).
     Time-kill testing of each of the microorganisms listed in
the 1994 TFM (59 FR 31402 at 31444) 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.
    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 of this type
on file from their own product development programs that has not been
submitted to the rulemaking. Furthermore, published data may be
available that would satisfy some or all of this data requirement.
2. In Vivo Studies
    Based on the recommendations of NDAC at its March 23, 2005,
meeting, we are continuing to propose the use of bacterial log
reductions as a means of demonstrating that health care antiseptics are
GRAE (Ref. 8). The 1994 TFM also proposed final formulation testing for
health care personnel hand washes (59 FR 31402 at 31448), surgical hand
scrubs (59 FR 31402 at 31445), and patient preoperative skin
preparations (59 FR 31402 at 31450). We do not discuss final
formulation testing here because we are not proposing that any of the
active ingredients are GRAS/GRAE. Although these proposed test methods
are intended to evaluate the effectiveness of antiseptic final
formulations, this type of clinical simulation testing when adequately
controlled also can be used to demonstrate that an active ingredient is
GRAE for use in a health care antiseptic product. Based on our
experience with the approval of NDA antiseptic products and input from
the March 2005 NDAC, we recommend that the bacterial log reduction
studies used to demonstrate that an active ingredient is GRAE for use
in health care antiseptic drug products include the following:
     A vehicle control to show the contribution of the active
ingredient to effectiveness. The test product should be statistically
superior to the vehicle control for the clinical simulation to be
considered successful at showing that the test product is effective for
use in health care antiseptic products. Products with vehicles that
have antimicrobial activity should consider using a negative control,
such as nonantimicrobial soap or saline, rather than a vehicle control.
     An active control to validate the study conduct to assure
that the expected results are produced. For the results to be valid,
the active control should meet the appropriate log reduction criteria.
     A sample size large enough to show statistically
significant differences from the results achieved using the vehicle,
and meeting the threshold of at least a 70 percent success rate for the
health care antiseptic, including justification that the number of
subjects tested is adequate for the test.
     Use of an appropriate neutralizer in all recovery media
(i.e., sampling solution, dilution fluid, and plating media) and a
demonstration of neutralizer validation. The purpose of neutralizer
validation is to show that the neutralizer used in the study is
effective against the test and control products, and that it is not
toxic to the test microorganisms. If a test product can be neutralized
through dilution, this should be demonstrated in the neutralizer
validation study.
     An analysis of the proportion of subjects who meet the log
reduction criteria based on a two-sided statistical test for
superiority to vehicle and a 95 percent confidence interval approach.
    To establish that a particular active ingredient is GRAE for use in
health care antiseptics, clinical simulation studies using the
parameters described in this section should be evaluated using log
reduction criteria similar to those proposed in the 1994 TFM (59 FR
31402 at 31445, 31448, and 31450). Our current criteria are laid out in
table 8. We have revised the log reduction criteria proposed for health
care personnel hand washes and rubs, and surgical hand scrubs and rubs
based on the recommendations of the March 2005 NDAC and comments to the
1994 TFM that argued that the demonstration of a cumulative antiseptic
effect for these products is unnecessary. We agree 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. For these indications, log reduction criteria are proposed only
for a single-product application rather than multiple-product
applications. Given that we are 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 applications. The GRAE
criteria proposed for all the health care antiseptic indications are
based on log reductions achieved by antiseptics as shown in the
published literature and evaluated under the NDA process. In addition,
based on the timeframes within which patient preoperative skin
preparations are commonly used, we are recommending that these products
also be able to demonstrate effectiveness at 30 seconds because we
believe that injections and some incisions might be made as soon as 30
seconds after skin preparation. The log reductions that we would expect
an effective health care antiseptic active ingredient to meet to show
that it is GRAE are shown in table 8.

      Table 8--Clinical Simulation Testing Bacterial Log Reduction
    Effectiveness Criteria in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
           Indication                  1994 TFM       This proposed rule
------------------------------------------------------------------------
Health care personnel hand wash    reduction  reduction of 2.5
 or health care personnel hand     of 2 log10 on       log10 on each
 rub.                              each hand within    hand within 5
                                   5 minutes after     minutes after a
                                   the first wash,     single wash or
                                   and                 rub.
                                   reduction
                                   of 3 log10 on
                                   each hand within
                                   5 minutes after
                                   the tenth wash.

Surgical hand scrub or surgical    reduction   reduction
 hand rub.                         of 1 log10 on       of 2 log10 on
                                   each hand within    each hand within
                                   1 minute after      1 minute after a
                                   the first wash on   single wash or
                                   day 1, and          rub, and
                                   does not    does not
                                   exceed baseline     exceed baseline
                                   at 6 hours on day   at 6 hours.
                                   1, and.
                                   reduction
                                   of 2 log10 on
                                   each hand within
                                   1 minute after
                                   the last wash on
                                   day 2, and.
                                   reduction
                                   of 3 log10 on
                                   each hand within
                                   1 minute after
                                   the last wash on
                                   day 5.
Patient preoperative skin          reduction   reduction
 preparation.                      of 2 log10 per      of 2 log10 per
                                   square centimeter   square centimeter
                                   on abdominal site   on abdominal site
                                   within 10 minutes   within 30 seconds
                                   after use, and      after use, and
                                   reduction   reduction
                                   of 3 log10 per      of 3 log10 per
                                   square centimeter   square centimeter
                                   on groin site       on groin site
                                   within 10 minutes   within 30 seconds
                                   after use, and.     after use, and
                                   does not    does not
                                   exceed baseline     exceed baseline
                                   at 6 hours.         at 6 hours.
------------------------------------------------------------------------

VII. Safety (Generally Recognized as Safe) Determination

    In the 1994 TFM, 11 active ingredients were classified as GRAS for
both health care personnel hand wash and surgical hand scrub use, and
18 active ingredients were classified as GRAS for patient preoperative
skin preparation use (59 FR 31402 at 31435). As described in section
I.C., health care personnel hand rubs and surgical hand rubs were not
separately addressed in the 1994 TFM. There have since been a number of
important scientific developments affecting our evaluation of the
safety of these active ingredients and causing us to reassess the data
necessary to support a GRAS determination. There is now new information
regarding systemic exposure to antiseptic active ingredients (Refs. 1
through 5). The potential for widespread antiseptic use to promote the
development of antibiotic-resistant bacteria also needs to be
evaluated. Further, additional experience with and knowledge about
safety testing has led to improved testing methods. Improvements
include study designs that are more capable of detecting potential
safety risks. Based on our reassessment, we are proposing new GRAS data
standards for health care antiseptic active ingredients. In order to
fully address these new safety concerns, additional safety data will be
necessary to support a GRAS determination for all health care
antiseptic active ingredients.
    Many of the safety considerations for the five health care
antiseptic uses are the same because each use is considered a
``chronic'' use as that term is defined by the International Conference
on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH).\3\ A use is considered chronic if
the drug will be used for a period of at least 6 months over the user's
lifetime, including repeated, intermittent use (Ref. 40). Health care
personnel washes and rubs are used on a frequent daily basis, as are
surgical hand scrubs and rubs. Health care authorities list a variety
of situations in which health care workers should perform hand hygiene,
such as before and after touching a patient, after contact with body
fluids, and after removing gloves (Refs. 21 and 23). Patient
preoperative skin preparations also are used daily by many users. For
example, many people with type I diabetes require three to four insulin
injections a day (Ref. 41) and use these products prior to each
injection. Accordingly, we are proposing the same safety testing for
each active ingredient be done to support a GRAS determination,
regardless of the proposed health care antiseptic use.
---------------------------------------------------------------------------

    \3\ FDA is a member of the ICH Steering Committee, the governing
body that oversees the harmonization activities, and contributed to
the development of ICH guidelines.
---------------------------------------------------------------------------

A. New Issues

    Since the 1994 TFM was published, new data have become available
indicating that systemic exposure to topical antiseptic active
ingredients may be greater than previously thought. Systemic exposure
refers to the presence of antiseptic active ingredients inside and
throughout the body. Because of advances in technology, our ability to
detect antiseptic active ingredients in body fluids such as serum and
urine is greater than it was in 1994. For example, studies have shown
detectable blood alcohol levels after use of alcohol-containing health
care personnel hand rubs or surgical hand rubs (Refs. 1, 4, and 5). We
believe that any consequences of this systemic exposure should be
identified and assessed to support our risk-benefit analysis for health
care antiseptic use.
    Given the frequent repeated use of both health care personnel hand
washes and rubs and surgical hand scrubs and rubs, systemic exposure
may occur. For some patients, the same may be true for patient
preoperative skin preparations. Although some systemic exposure data
exist for alcohol and triclosan, many of the other health care
antiseptic active ingredients have not been evaluated in this regard.
Currently, there is also a lack of data to assess the impact of
important drug use factors that can influence systemic exposure such as
dose, application frequency, application method, duration of exposure,
product formulation, skin condition, and age.
    The evaluation of the safety of drug products involves correlating
findings from animal toxicity studies to the level of drug exposure
obtained from pharmacokinetic studies in animals and humans. Our
administrative record lacks the data necessary to define a margin of
safety for the potential chronic use of health care antiseptic active
ingredients. Thus, we are continuing to propose that both animal and
human pharmacokinetic data are necessary for health care antiseptic
active ingredients. This information will help identify any potential
safety concerns and help determine the safety margin for OTC human use.
    One potential effect of systemic exposure to health care antiseptic
active ingredients that has come to our attention since publication of
the 1994 TFM is data suggesting that some health care antiseptic active
ingredients have hormonal effects. Triclosan and triclocarban can cause
alterations in

thyroid and reproductive systems of neonatal and adolescent animals
(Refs. 42 through 51). Hormonally active compounds have been shown to
affect not only the exposed organism, but also subsequent generations
(Ref. 52). These effects may not be related to direct deoxyribonucleic
acid (DNA) mutation, but rather to alterations in factors that regulate
gene expression (Ref. 53).
    A hormonally active compound that causes reproductive system
disruption in the fetus or infant may have effects that are not
apparent until many years after initial exposure. There are also
critical times in fetal development when a change in hormonal balance
that would not cause any lasting effect in an adult could cause a
permanent developmental abnormality in a child. For example, untreated
hypothyroidism during pregnancy has been associated with cognitive
impairment in the offspring (Refs. 54, 55, and 56).
    Because health care antiseptics are chronic use products and are
used by sensitive populations such as pregnant women, evaluation of the
potential for chronic toxicity and effects on reproduction and
development should be included in the safety assessment. The designs of
general toxicity and reproductive/developmental studies are often
sufficient to identify developmental effects that can be caused by
hormonally active compounds through the use of currently accepted
endpoints and standard good laboratory practice toxicology study
designs. As followup in some cases, additional study endpoints may be
needed to fully characterize the potential effects of drug exposure on
the exposed individuals. Section VII.C describes the types of studies
that can adequately evaluate an active ingredient's potential to cause
developmental or reproductive toxicity, or adverse effects on the
thyroid gland.

B. Antimicrobial Resistance

    Since publication of the 1994 TFM, there is new information
available concerning the impact of widespread antiseptic use on the
development of antimicrobial resistance (Refs. 57 through 60). Bacteria
use some of the same resistance mechanisms against both antiseptics and
antibiotics. Thus, the use of antiseptic active ingredients with
resistance mechanisms in common with antibiotics may have the potential
to select for bacterial strains that are also resistant to clinically
important antibiotics, adding to the problem of antibiotic resistance.
In the health care setting where infection-control practices are
multifaceted and include the use of antiseptics, antibiotics, and
frequent disinfection, it is difficult to identify the source of
antimicrobial resistance or to quantify the impact of antiseptics on
the selection, survival, and spread of antimicrobial resistant
bacterial strains.
    Laboratory studies of some of the antiseptic active ingredients
evaluated in this proposed rule demonstrate that bacteria can develop
reduced susceptibility to antiseptic active ingredients and some
antibiotics after growth in nonlethal amounts of the antiseptic (i.e.,
low-to-moderate concentrations of antiseptic) (Refs. 61 through 78).
These studies indicate that further data needs to be gathered regarding
whether bacterial resistance mechanisms exist that could select for
cross-resistance in the health care setting.
    Laboratory studies examining the antiseptic and antibiotic
susceptibilities of clinical isolates of Staphylococcus aureus and
methicillin-resistant S. aureus (MRSA) have found strains of these
organisms with reduced susceptibilities to both antiseptics and
antibiotics (Refs. 67 and 79 through 83). However, the impact of such
dual tolerances in the clinical setting is unclear. Studies of the
impact of such tolerance in S. aureus and Escherichia coli in the
clinical setting have yielded mixed results (Refs. 84 through 87).
Interpretation of these data is further limited by the fact that only
S. aureus and E. coli have been studied. All of the organisms studied
constitute a very small subset of the organisms of concern, and one of
these organisms (MRSA) is already resistant to some antimicrobials.
Thus, the available data are not sufficient to support a finding that
these mechanisms of reduced susceptibility would have meaningful
clinical impact in a setting where extensive infection control measures
that include antibiotic use and frequent disinfection are the norm. In
other words, bacteria in the health care setting will be exposed to
multiple sources of antimicrobials--regardless of the use of health
care antiseptics--which may lessen the impact of the role of health
care antiseptics in the development of bacterial resistance.
    FDA has been evaluating the role that all antiseptic products,
including health care antiseptic products, may play in the development
of antibiotic resistance for quite some time, and has sought the advice
from expert panels on this topic. In 1997, a joint Nonprescription
Drugs and Anti-Infective Drugs Advisory Committee concluded that the
data were not sufficient to take any action on this issue at that time
(Ref. 6). The joint Committee recommended that FDA work with industry
to establish surveillance mechanisms to address antiseptic and
antibiotic resistance. FDA also plays a major role on the Interagency
Task Force on Antimicrobial Resistance and helped draft the Public
Health Action Plan to Combat Antimicrobial Resistance (Ref. 88). The
Action Plan discusses how to sufficiently implement the surveillance,
prevention and control, and research elements of the Action Plan.
    Reports of the persistence of low levels of some antiseptic active
ingredients in the environment (Refs. 89, 90, and 91) signal the need
to better understand the impact of all antiseptics, including health
care antiseptic drug products. Although it is important to consider the
relative contribution of the use of health care antiseptic products to
any possible environmental impact, it is also important to consider the
benefits of these products. Hospital-acquired infections can result in
prolonged hospital stays, additional medical treatment, adverse
clinical outcomes, and increased health care costs. The use of health
care antiseptics is considered an important component of the
multifaceted approach that hospitals use to keep hospital acquired
infection rates low (Refs. 21 and 23). Furthermore, in situations where
there is extensive use of antibiotics, exposure to antibiotics, rather
than exposure to antiseptics, plays a dominant role in emerging
antibiotic resistance. This makes it difficult to determine whether
antiseptics play a significant role in the development of antimicrobial
resistance in the hospital setting. Despite this, the use of
antiseptics in health care settings may also contribute to the
selection of bacterial genera and species that are less susceptible to
both antiseptics and antibiotics. We are requesting additional data and
information to address this issue. Section VII.C describes the data
that will help establish a better understanding of the interactions
between antiseptic active ingredients and bacterial resistance
mechanisms in health care antiseptic products and will provide the
information needed to perform an adequate risk assessment for these
health care product uses. FDA recognizes that the science of evaluating
the potential of compounds to cause bacterial resistance is evolving
and acknowledges the possibility that alternative data different from
that listed in section VII.C may be identified as an appropriate
substitute for evaluating resistance.

C. Studies To Support a Generally Recognized as Safe Determination

    A GRAS determination for health care antiseptic active ingredients
must be

supported by both nonclinical (animal) and clinical (human) studies. To
issue a final monograph for these products, this safety data must be in
the administrative record (i.e., rulemaking docket).\4\
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    \4\ At the 2014 NDAC meeting, FDA received comments referencing
data or other information that appears to be relevant to the safety
assessment of health care antiseptic active ingredients, but the
referenced data and information were not submitted to the docket for
this rulemaking and we are not aware that it is otherwise publicly
available. The Agency will consider only material that is submitted
to the docket for this rulemaking or that is otherwise publicly
available in its evaluation of the GRAS/GRAE status of a relevant
ingredient. Information about how to submit such data or information
to the docket is set forth in this document in the ADDRESSES
section.
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    To assist manufacturers or others who wish to provide us with the
information we expect will establish GRAS status for these active
ingredients, we are including specific information, based in part on
existing FDA guidance, about the other kinds of studies to consider
conducting and submitting. We have published guidance documents
describing the nonclinical safety studies that a manufacturer should
perform when seeking to market a drug product under an NDA (Refs. 40
and 92 through 98). These guidance documents also provide relevant
guidance for performing the nonclinical studies necessary to determine
GRAS status for a health care antiseptic active ingredient. Because
health care antiseptics may be used repeatedly and in sensitive
populations, we propose that health care antiseptic active ingredients
will need to be tested for carcinogenic potential, developmental and
reproductive toxicity (DART), and other potential effects as described
in more detail in this section.
1. FDA Guidances Describing Safety Studies
    The safety studies that are described in the existing FDA guidances
(Refs. 40 and 92 through 98) provide a framework for the types of
studies that are needed for FDA to assess the safety of each antiseptic
active ingredient according to modern scientific standards and make a
GRAS determination. A description of each type of study and how we
would use this information to improve our understanding of the safety
of health care antiseptic active ingredients is provided in table 9.

           Table 9--FDA Guidance Documents Related to Requested Safety Data and Rationale for Studies
----------------------------------------------------------------------------------------------------------------
            Type of study                  Study conditions      What the data tell us    How the data are used
----------------------------------------------------------------------------------------------------------------
Animal pharmacokinetic absorption,     Both oral and dermal     Allows identification    Used as a surrogate to
 distribution, metabolism, and          administration.          of the dose at which     identify toxic
 excretion (ADME) (Refs. 93 and 99).                             the toxic effects of     systemic exposure
                                                                 an active ingredient     levels that can then
                                                                 are observed as a        be correlated to
                                                                 result of systemic       potential human
                                                                 exposure of the drug.    exposure via dermal
                                                                 ADME data provide: The   pharmacokinetic study
                                                                 rate and extent an       findings. Adverse
                                                                 active ingredient is     event data related to
                                                                 absorbed into the body   particular doses and
                                                                 (e.g., AUC, Cmax,        drug levels (exposure)
                                                                 Tmax); \1\ where the     in animals are used to
                                                                 active ingredient is     help formulate a
                                                                 distributed in the       safety picture of the
                                                                 body; whether            possible risk to
                                                                 metabolism of the        humans.
                                                                 active ingredient by
                                                                 the body has taken
                                                                 place; information on
                                                                 the presence of
                                                                 metabolites; and how
                                                                 the body eliminates
                                                                 the original active
                                                                 ingredient (parent)
                                                                 and its metabolites
                                                                 (e.g., T\1/2\). \2\.
Human pharmacokinetics (MUsT) (Ref.    Dermal administration    Helps determine how      Used to relate the
 97).                                   using multiple           much of the active       potential human
                                        formulations under       ingredient penetrates    exposure to toxic drug
                                        maximum use conditions.  the skin, leading to     levels identified in
                                                                 measurable systemic      animal studies.
                                                                 exposure.
Carcinogenicity (ICH S1A, S1B, and     Minimum of one oral and  Provides a direct        Identifies the systemic
 S1C (Refs. 40, 92, and 95)).           one dermal study for     measure of the           and dermal risks
                                        topical products.        potential for active     associated with drug
                                                                 ingredients to cause     active ingredients.
                                                                 tumor formation          Taken together, these
                                                                 (tumorogenesis) in the   studies are used to
                                                                 exposed animals.         identify the type(s)
                                                                                of toxicity, the level
                                                                                of exposure that
                                                                                produces these
                                                                                toxicities, and the
                                                                                highest level of
                                                                                exposure at which no
                                                                                adverse effects occur,
                                                                                referred to as the
                                                                                ``no observed adverse
                                                                                effect level''
                                                                                (NOAEL). The NOAEL is
                                                                                used to determine a
                                                                                safety margin for
                                                                                human exposure.
Developmental toxicity (ICH S5 (Ref.   Oral administration....  Evaluates the effects
 94)).                                                           of a drug on the
                                                                 developing offspring
                                                                 throughout gestation
                                                                 and postnatally until
                                                                 sexual maturation.
Reproductive toxicity (ICH S5 (Ref.    Oral administration....  Assesses the effects of
 94)).                                                           a drug on the
                                                                 reproductive
                                                                 competence of sexually
                                                                 mature male and female
                                                                 animals.
Hormonal effects (Ref. 98)...........  Oral administration....  Assesses the drug's      Used in hazard
                                                                 potential to interfere   assessment to
                                                                 with the endocrine       determine whether the
                                                                 system.                  drug has the capacity
                                                                                to induce a harmful
                                                                                effect at any exposure
                                                                                level without regard
                                                                                to actual human
                                                                                exposures.
----------------------------------------------------------------------------------------------------------------
\1\ ``AUC'' denotes the area under the concentration-time curve, a measure of total exposure or the extent of
  absorption. ``Cmax'' denotes the maximum concentration, which is peak exposure. ``Tmax'' denotes the time to
  reach the maximum concentration, which aids in determining the rate of exposure.
\2\ ``T\1/2\'' denotes the half-life, which is the amount of time it takes to eliminate half the drug from the
  body or decrease the concentration of the drug in plasma by 50 percent.

    These studies represent FDA's current thinking on the data needed
to support a GRAS determination for an OTC antiseptic active ingredient
and are similar to those recommended by the Antimicrobial I Panel
(described in the ANPR (39 FR 33103 at 33135)) as updated by the
recommendations of the 2014 NDAC. However, even before the 2014 NDAC
meeting, the Panel's recommendations for data to support the safety of
an OTC topical

antimicrobial active ingredient included studies to characterize the
following:
 Degree of absorption through intact and abraded skin and
mucous membranes
 Tissue distribution, metabolic rates, metabolic fates, and
rates and routes of elimination
 Teratogenic and reproductive effects
 Mutagenic and carcinogenic effects
2. Studies To Characterize Maximal Human Exposure
    Because the available data indicate that some dermal products,
including at least some antiseptic active ingredients, are absorbed
after topical application in humans and animals, it is necessary to
assess the effects of long-term dermal and systemic exposure to these
ingredients. Based on input from the 2014 NDAC meeting, the Agency has
also determined that results from a human pharmacokinetic (PK) maximal
usage trial (MUsT) are needed to support a GRAS determination. This
trial design is also referred to as a maximal use PK trial and is
described in FDA's 2005 draft guidance for industry on developing drugs
for treatment of acne vulgaris (Ref. 97). The purpose of the MUsT is to
evaluate systemic exposure under conditions that would maximize the
potential for drug absorption in a manner consistent with possible
``worst-case'' real world use of the product. In a MUsT, the collected
plasma samples are analyzed, and the resulting in vivo data could be
used to estimate a safety margin based on animal toxicity studies.
    A MUsT to support a determination that an active ingredient is GRAS
for use in health care antiseptics is conducted by obtaining an
adequate number of PK samples following administration of the active
ingredient. For studies of active ingredients to be used in topically
applied products like these that are used primarily on adults, for
which there is less information available and for which crossover
designs are not feasible, a larger number of subjects are required
compared to studies of orally administered drug products. A MUsT using
50 to 75 subjects should be sufficient to get estimates of the PK
parameters from a topically applied health care antiseptic. The MUsT
should attempt to maximize the potential for drug absorption to occur
by considering the following design elements (Ref. 100):
     Adequate number of subjects (steps should be taken to
ensure that the target population (for example, age, gender, race) is
properly represented);
     frequency of dosing (e.g., number of hand rub applications
during the study);
     duration of dosing (e.g., dosing to represent an 8- to 12-
hour health care worker shift);
     use of highest proposed strength (e.g., 95 percent
alcohol);
     total involved surface area to be treated at one time
(e.g., hands and arms up to the elbow for surgical hand scrubs and
rubs);
     amount applied per square centimeter
     method of application (e.g., hand rub or hand wash); and
     sensitive and validated analytical methods.
    It also is important that the MUsT reflect maximal use conditions
of health care antiseptics (Ref. 101) using different formulations to
fully characterize the active ingredient's potential for dermal
penetration. Since real-world exposure from health care personnel hand
wash and rub and surgical hand scrub and rub use is likely to be
greater than from patient preoperative skin preparation use, MUsT data
on an active ingredient for either of these indications also would be
sufficient to fulfill the MUsT requirement for a patient preoperative
skin preparation.
3. Studies To Characterize Hormonal Effects
    We propose that data are also needed to assess whether health care
antiseptic active ingredients have hormonal effects that could produce
developmental or reproductive toxicity. A hormonally active compound is
a substance that interferes with the production, release, transport,
metabolism, binding, activity, or elimination of natural hormones,
which results in a deviation from normal homeostasis, development, or
reproduction (Ref. 102). Exposure to a hormonally active compound early
in development can result in long-term or delayed effects, including
neurobehavioral, reproductive, or other adverse effects.
    There are several factors common to antiseptic products that make
it necessary to assess their full safety profile prior to classifying
an antiseptic active ingredient as GRAS for use in health care
antiseptic products. These factors are as follows:
     Evidence of systemic exposure to several of the antiseptic
active ingredients.
     Exposure to multiple sources of antiseptic active
ingredients that may be hormonally active compounds, in addition to
exposure to health care antiseptic products.
     Exposure to antiseptic active ingredients may be long-term
for some health care professionals.
    Most antiseptic active ingredients have not been evaluated for
hormonal effects despite the fact that several of the ingredients have
evidence of systemic absorption. For antiseptic active ingredients that
have not been evaluated, in vitro receptor binding or enzyme assays can
provide a useful preliminary assessment of the potential hormonal
activity of an ingredient. However, these preliminary assays do not
provide conclusive evidence that such an interaction will lead to a
significant biological change (Ref. 103). Conversely, lack of binding
does not rule out an effect (e.g., compounds could affect synthesis or
metabolism of a hormone, resulting in drug-induced changes in hormone
levels indirectly).
    a. Traditional studies. General nonclinical toxicity and