[Federal Register Volume 81, Number 126 (Thursday, June 30, 2016)]
[Proposed Rules]
[Pages 42911-42937]
[FR Doc No: 2016-15410]

Vol. 81

Thursday,

No. 126

June 30, 2016

Part IV

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 Consumer 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. 81 , No. 126 / Thursday, June 30, 2016 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2016-N-0124 (Formerly Part of Docket No. FDA-1975-N-
0012)]
RIN 0910-AF69

Safety and Effectiveness of Consumer 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 or Agency) 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 consumer antiseptic products intended for
use without water (referred to throughout as consumer antiseptic rubs
or consumer rubs) are generally recognized as safe and generally
recognized as effective (GRAS/GRAE). In the 1994 TFM, certain
antiseptic active ingredients were proposed as being GRAS for
antiseptic rub use by consumers 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 and changes in the use
patterns of these products, we are now proposing that additional safety
data are necessary to support the safety of antiseptic active
ingredients for this use. We also are proposing that all consumer
antiseptic rub 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 December 27, 2016. See
section IX of this document for the proposed effective date of a final
rule based on this proposed rule.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to http://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions''). We
note however, that the OTC drug monograph process is a public process;
and, the Agency intends to consider only non-confidential material that
is submitted to the docket for this rulemaking or that is otherwise
publicly available in evaluating if a relevant ingredient is GRAS/GRAE.

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of
Dockets Management, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2016-N-0124 for ``Safety and Effectiveness of Consumer Antiseptics;
Topical Antimicrobial Drug Products for Over-the-Counter Human Use;
Proposed Amendment of the Tentative Final Monograph; Reopening of
Administrative Record.'' Received comments will be placed in the docket
and, except for those submitted as ``Confidential Submissions,''
publicly viewable at http://www.regulations.gov or at the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. If you do not
wish your name and contact information to be made publicly available,
you can provide this information on the cover sheet and not in the body
of your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or
the electronic and written/paper 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.

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

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Regulatory Action
    B. Summary of the Major Provisions of the Regulatory Action in
Question
    C. Effectiveness
    D. Safety
    E. Active Ingredients
    F. Costs and Benefits
II. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

    D. Comment Period
III. Background
    A. Significant Rulemakings Relevant to This Proposed Rule
    B. Public Meetings Relevant to This Proposed Rule
    C. Comments Received by FDA
IV. 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 the OTC Drug
Review
V. Ingredients Previously Proposed as Not Generally Recognized as
Safe and Effective
VI. Summary of Proposed Classifications of OTC Consumer Antiseptic
Rub Active Ingredients
VII. Effectiveness (Generally Recognized as Effective) Determination
    A. Evaluation of Effectiveness Data
    B. Current Standards: Studies Needed To Support a Generally
Recognized as Effective Determination
    C. Impact of Application Parameters on Efficacy
VIII. 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
IX. Proposed Effective Date
X. Summary of Preliminary Regulatory Impact Analysis
A. Introduction
    B. Summary of Costs and Benefits
    XI. Paperwork Reduction Act of 1995
XII. Environmental Impact
XIII. Federalism
XIV. References

I. Executive Summary

A. 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 active
ingredients used in OTC consumer antiseptic products intended to be
used without water are GRAS/GRAE based on FDA's reevaluation of the
safety and effectiveness data requirements proposed in the 1994 TFM for
what were then referred to as antiseptic hand washes (which included
the products we refer to in this document as consumer antiseptic rubs
or consumer rubs). We are conducting this reevaluation based on the
comments received, input from subsequent public meetings, and our
independent evaluation of other relevant scientific information we have
identified and placed in the docket. This proposed rule applies to
active ingredients used in consumer antiseptic rub products that are
sometimes referred to as rubs, leave-on products, or hand
``sanitizers,'' as well as to consumer antiseptic wipes. These products
are intended to be used when soap and water are not available, and are
left on and not rinsed off with water. We will refer to them here as
consumer antiseptic rubs or consumer rubs. In separate rulemakings (78
FR 76444, December 17, 2013; 80 FR 25166, May 1, 2015), we proposed
conditions under which OTC consumer antiseptic washes and OTC
antiseptics intended for use by health care professionals in a hospital
setting or other health care situation outside the hospital are GRAS/
GRAE. Those antiseptic products are not addressed in this proposed
rule.

B. 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 rub
active ingredients intended for use by consumers. The effectiveness
data, the safety data, and the effect on the previously proposed
classification of active ingredients are described briefly in this
summary. Because no ingredients currently meet the criteria for a GRAS/
GRAE determination in this proposed rule, this rulemaking does not
specifically address requirements for anticipated final formulation
testing (i.e., testing the mixture of both active and inactive
ingredients proposed for marketing) or labeling. Final formulation
testing could potentially involve both efficacy testing and safety
testing to determine absorption. It is anticipated that if a final rule
includes any GRAS/GRAE ingredients, labeling will be addressed as part
of the final rule and may include elements related to application
volume and safety labeling for children, including a warning to keep
out of reach of children. We anticipate that specific effectiveness
claims in labeling will reflect the testing performed in support of
these claims. Effectiveness testing using surrogate endpoints as
described in this proposed rule is designed to support antibacterial
claims.

C. Effectiveness

    A determination that a drug product containing a particular active
ingredient would be GRAE for a particular intended use requires
consideration of the benefit-to-risk ratio for the drug under the
specified conditions of use. New information on potential risks posed
by the use of certain consumer antiseptic products, as well as input
from the Nonprescription Drugs Advisory Committee (NDAC) that met in
March 2005 (the March 2005 NDAC) and October 2005 (the October 2005
NDAC), has prompted us to reevaluate the data needed for classifying
active ingredients used in consumer rubs as GRAE. The reevaluation of
effectiveness will help to ensure that the level of effectiveness
achieved is adequate to offset newly identified safety concerns (see
new information described in the safety section of this executive
summary). We continue to propose the use of surrogate endpoints
(bacterial log reductions) as a demonstration of effectiveness for
consumer antiseptic rubs combined with in vitro testing to characterize
the antimicrobial activity of the ingredient. However, the log
reductions required for the demonstration of effectiveness for consumer
rubs have been revised based on the recommendations of the March 2005
and October 2005 NDAC meetings, comments received after the 1994 TFM,
and other information we reviewed.
    We have evaluated the available literature, the data, and other
information that were submitted to the rulemaking on the effectiveness
of consumer rub active ingredients, as well as the recommendations from
the public meetings held by the Agency on antiseptics. We propose that
the record contain additional log reduction data to demonstrate the
effectiveness of consumer rub active ingredients. We are also asking
for data and information to be submitted about the impact of product
use factors (such as volume of product per application) on efficacy to
help inform labeling and requirements for final formulation testing.

D. Safety

    Several important scientific developments that affect the safety
evaluation of consumer rub active ingredients have occurred since FDA's
1994 evaluation of the safety of these 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 consumer antiseptic rub 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. These data are particularly important given the
increased use of consumer antiseptic rubs since the publication of

the 1994 TFM. 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 consumer antiseptic rub 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 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 consumer antiseptic rub
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 consumer antiseptic rub 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 consumer antiseptic rub products
in light of the new safety information. Consumers may use antiseptic
rubs on a daily, long-term (i.e., chronic) basis. The data we propose,
which are needed to demonstrate safety for all consumer antiseptic rub
active ingredients, fall into two broad categories: (1) Human safety
studies and (2) nonclinical safety studies. For one of the consumer
antiseptic rub active ingredients (benzalkonium chloride), data to
evaluate the development of antimicrobial resistance also is required
to demonstrate its safety.

E. Active Ingredients

    Three active ingredients are being evaluated for use as a consumer
antiseptic rub in this proposed rule: Alcohol (ethanol or ethyl
alcohol), isopropyl alcohol, and benzalkonium chloride (sometimes
referred to as ADBAC). As part of this proposed rule, FDA evaluated new
data submitted after publication of the 1994 TFM for each of these
three ingredients.
    In the 1994 TFM (59 FR 31402 at 31435), alcohol (60 to 95 percent)
was proposed to be classified as GRAS/GRAE (59 FR 31402 at 31435 to
31436) for use as what was then called an antiseptic hand wash (a use
which included both products intended to be rinsed off (washes) and
those intended to be left on (rubs)). Isopropyl alcohol (70 to 91.3
percent) was proposed to be categorized in Category III in the 1994 TFM
because of a lack of adequate effectiveness data for use as an
antiseptic hand wash (59 FR 31402 at 31435 to 31436). However, we now
propose that both alcohol and isopropyl alcohol need additional safety
and effectiveness data to support a classification of GRAS/GRAE for
consumer antiseptic rub use. Our detailed evaluation of the
effectiveness and safety of the active ingredients for which data were
submitted can be found in sections VII.A and VIII.D.
    In the 1994 TFM, FDA categorized benzalkonium chloride in Category
III because of a lack of adequate safety and effectiveness data for its
use as an antiseptic hand wash (59 FR 31402 at 31435). We have
evaluated safety data received in response to the 1994 TFM and the
consumer antiseptic wash proposed rule published in the Federal
Register of December 17, 2013 (78 FR 76444) (2013 Consumer Wash
Proposed Rule (PR)) (see section VIII.D). In this proposed rule, we
propose that benzalkonium chloride needs additional safety and
effectiveness data to support a classification of GRAS/GRAE for
consumer antiseptic rub use.
    If we do not receive sufficient data to support monograph
conditions for consumer antiseptic rub products containing these active
ingredients, these active ingredients may not be included in the future
OTC consumer antiseptic rub final monograph. Any consumer antiseptic
rub product containing the active ingredients being considered under
this rulemaking that are not included in a future final monograph could
seek 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, NDA
deviations might be submitted for these products in accordance with 21
CFR 330.11, limiting the scope of review necessary to obtain approval.

F. Costs and Benefits

    The impact of the proposed rule on the OTC consumer antiseptic rub
product industry will depend on the outcome of tests to determine
whether three antiseptic ingredients--alcohol, isopropyl alcohol, and
benzalkonium chloride--are GRAS/GRAE. It is possible that none, one,
two, or all three of the ingredients will be determined to be GRAS/
GRAE. We consider two extreme scenarios to capture the entire range of
total costs: (1) All three ingredients are deemed to be GRAS/GRAE or
(2) none of the ingredients is deemed to be GRAS/GRAE.
    The range of estimated costs is wide because the number of products
that would need to be reformulated and relabeled depends on whether or
not an antiseptic ingredient is deemed to be GRAS/GRAE. A small number
of products contain active ingredients which FDA has determined are not
eligible for use in consumer antiseptic rubs and these products will
need to be reformulated and relabeled (scenario 1). However, in
scenario 2 (and intermediate scenarios), the resulting costs are higher
because a greater number of products will need to be reformulated and
relabeled as a result of tests failing to show GRAS/GRAE status.
    The total upfront costs of the proposed regulation--which include
the expenditures to reformulate and relabel products that contain
nonmonograph ingredients--are estimated to range from $0.34 million to
$1.02 million for scenario 1 and from $15.99 million to $47.09 million
for scenario 2. Annualizing upfront costs over a 10-year period at a
discount rate of 3% for scenario 1, the costs of the proposed rule are
estimated to be between $0.04 million and $0.12 million per year; the
corresponding estimated cost at a discount rate of 7% is between $0.05
million and $0.14 million per year. In scenario 2, none of the
ingredients is determined to be GRAS/E and we expect that manufacturers
will reformulate their products to be free of antiseptics and relabel
them to reflect the change in ingredients. Annualizing upfront costs
over a 10-year period at a discount rate of 3% for scenario 2, the
costs of the proposed rule are estimated to be between $1.87 million
and $5.52 million per year; the corresponding estimated cost at a
discount rate of 7% is between $2.28 million and $6.70 million per
year. We assume that health risk falls with reduced exposure to
potentially unsafe or ineffective antiseptic ingredients in consumer
antiseptic rubs. We estimate that the proposed rule will reduce
exposure to potentially unsafe or ineffective antiseptic ingredients in
consumer antiseptic rubs by between 110 and 67,272,847 pounds.\1\
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    \1\ As was the case with estimated costs, there is a great
disparity in the estimated reductions in exposure to antiseptic
ingredients. The lower bound (110 pounds) represents the estimated
reduction in exposure to ingredients which FDA has determined are
not GRAS/GRAE for use in consumer antiseptic rubs and few products
contain such GRAS/GRAE ingredients.

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                                  Total reduction in
 Summary of costs and benefits   antiseptic ingredient  Total costs annualized over    Total one-time costs (in
     of the proposed rule        exposure (in pounds)      10 years (in millions)             millions)
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Total.........................  110 and 67,272,847....  $0.04 to $5.52 (3%)........  $0.34 and $47.09.
                                                        $0.05 to $6.70 (7%)........
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II. 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 consumer antiseptic rubs 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 (21 CFR 330.10)), the September 1974 advance notice of
proposed rulemaking (39 FR 33103, September 13, 1974) (1974 ANPR) was
designated as a ``proposed monograph.'' Similarly, the notices of
proposed rulemaking, which were published in the Federal Register of
January 6, 1978 (43 FR 1210) (the 1978 TFM), and in the Federal
Register of June 17, 1994 (59 FR 31402) (the 1994 TFM), were each
designated as a ``tentative final monograph'' (see table 1 in section
III.A). The present proposed rule, which is a proposal to amend the
1994 TFM with respect to consumer antiseptic rub 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 (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. The 1974 ANPR covered seven different intended uses for these
products: (1) Antimicrobial soap; (2) health care personnel hand wash;
(3) patient preoperative skin preparation; (4) skin antiseptic; (5)
skin wound cleanser; (6) skin wound protectant; and (7) surgical hand
scrub (39 FR 33103 at 33140). FDA subsequently identified skin
antiseptics, skin wound cleansers, and skin wound protectants as
antiseptics used primarily by consumers for first aid use and referred
to them collectively as ``first aid antiseptics.'' We published a
separate TFM covering 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.
    In the 1974 ANPR, we distinguished antimicrobial soaps used by
consumers from professional use antiseptics, such as health care
personnel hand washes. (See section II.C about the term ``antimicrobial
soaps.'') In contrast, in the 1994 TFM, we proposed that both
antiseptic hand washes (i.e., consumer antiseptic 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 agreed, and in the 2013 Consumer Wash PR and in the
health care antiseptic proposed rule published in the Federal Register
of May 1, 2015 (80 FR 25166) (2015 Health Care Antiseptic PR), our
evaluation of OTC antiseptic drug products has been further subdivided
into consumer antiseptics and health care antiseptics, which are used
by health care professionals in a hospital setting or other health care
situations outside the hospital. 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
rubs or washes). Furthermore, the purpose of use is generally
different; health care antiseptics are primarily used to protect the
patient (rather than just the user), whereas consumer antiseptics are
generally applied to protect the user. 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.
    As we did in the 2013 Consumer Wash PR, we refer to the group of
products covered by this proposed rule as ``consumer antiseptics.''
Consumer antiseptic drug products addressed by this proposal include
consumer antiseptic hand rubs (commonly called hand sanitizers) and
antiseptic wipes.

These products may be used by consumers for personal use on a frequent
basis, even multiple times per day. These products do not include
personal care products intended to be used with water, such as
antibacterial soaps, hand washes, and body washes.

C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

    In this proposed rule, FDA proposes the establishment of a
monograph for OTC consumer antiseptics that are intended for use as an
antiseptic rub, but that are not identified as ``first aid
antiseptics'' in the 1991 First Aid TFM. When the 1994 TFM was
published, the term for daily consumer use antiseptics was changed to
``antiseptic hand wash.'' In response to this change, we received
comments that the term ``antiseptic hand wash'' did not include all of
the consumer products on the market, such as hand rubs and body washes.
Therefore, in this proposed rule, we use the term ``consumer
antiseptic,'' which is a broad term and meant to include all of the
types of antiseptic products used on a frequent or daily basis by
consumers. However, this proposed rule covers only consumer antiseptic
rubs and does not include consumer antiseptic hand washes or body
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
consumer hand washes and body washes, and 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. They are
intended to be used when soap and water are not available. Consumer
antiseptic rubs include ``hand sanitizers'' and wipes. The 1994 TFM
also did not distinguish between consumer antiseptic washes and rubs,
and health care hand washes and rubs. This proposed rule covers only
consumer antiseptic rubs. Completion of the monograph for consumer
antiseptic rubs and certain other monographs for the active ingredient
triclosan are subject to a Consent Decree entered by the U.S. District
Court for the Southern District of New York on November 21, 2013, in
Natural Resources Defense Council, Inc. v. United States Food and Drug
Administration, et al., 10 Civ. 5690 (S.D.N.Y.).

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 (see ADDRESSES)
within 12 months of publication, and comments on any new data or
information may then be submitted to the docket for an additional 60
days (see Sec.  330.10(a)(7)(iii) and (iv)). In addition, FDA will also
consider requests to defer further rulemaking with respect to a
specific active ingredient for use as a consumer antiseptic rub to
allow the submission of new safety or effectiveness data to the record
if these requests are submitted to the docket within the initial 180-
day 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 GRAS/GRAE determination.
    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. In
addition, 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.

III. 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 publications
relevant to this proposed rule are available at http://www.regulations.gov in FDA Docket No. 1975-N-0012.

          Table 1--Significant Rulemaking Publications Related to Consumer Antiseptic Drug Products \1\
----------------------------------------------------------------------------------------------------------------
                     Federal Register Notice                                   Information in notice
----------------------------------------------------------------------------------------------------------------
1974 ANPR (September 13, 1974, 39 FR 33103)......................  We published an ANPR 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, 1978, 43 FR 1210).............  We published our tentative 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, 47 FR 22324)....................  We published an ANPR 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.
1991 First Aid TFM (July 22, 1991, 56 FR 33644)..................  We amended the 1978 TFM to establish 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 (June 17, 1994, 59 FR 31402).....  We amended the 1978 TFM to establish 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 (December 17, 2013, 78 FR        We issued a proposed rule to amend the 1994
 76444).                                                            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.
2015 Health Care Antiseptics TFM (May 1, 2015, 80 FR 25166 ).....  We issued a proposed rule to amend the 1994
                                                                    TFM and to establish data standards for
                                                                    determining whether OTC health care
                                                                    antiseptics are GRAS/GRAE.
                                                                   In that proposed rule, we proposed that
                                                                    additional safety and effectiveness data are
                                                                    necessary to support the safety and
                                                                    effectiveness of health care antiseptic
                                                                    active ingredients.
----------------------------------------------------------------------------------------------------------------
\1\ The publications listed in table 1 can be found at the FDA's ``Status of OTC Rulemakings'' Web site
  available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications dated after 1993 can also be found in the Federal
  Register at https://www.federalregister.gov.

B. Public Meetings Relevant to This Proposed Rule

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

                                        Table 2--Relevant Public Meetings
----------------------------------------------------------------------------------------------------------------
                     Date and type of meeting                                   Topic of discussion
----------------------------------------------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint meeting with the Anti-Infective   Antiseptic and antibiotic resistance in
 Drugs Advisory Committee) (January 6, 1997, 62 FR 764).            relation to an industry proposal for
                                                                    consumer and health care antiseptic
                                                                    effectiveness testing (Health Care Continuum
                                                                    Model) (Refs. 6, 7).
March 2005 NDAC Meeting (February 18, 2005, 70 FR 8376)..........  The use of surrogate endpoints and study
                                                                    design issues for the in vivo testing of
                                                                    health care antiseptics (Ref. 8).
October 2005 NDAC Meeting (September 15, 2005, 70 FR 54560)......  Benefits and risks of consumer antiseptics.
                                                                    NDAC expressed concern about the pervasive
                                                                    use of consumer antiseptic washes where
                                                                    there are potential risks and no
                                                                    demonstrable benefit. To demonstrate a
                                                                    clinical benefit, NDAC recommended clinical
                                                                    outcome studies to show that antiseptic
                                                                    washes are superior to nonantibacterial soap
                                                                    and water (Ref. 9).
November 2008 Public Feedback Meeting............................  Demonstration of the effectiveness of
                                                                    consumer antiseptics (Ref. 10).
September 2014 NDAC Meeting (July 29, 2014, 79 FR 44042).........  Safety testing framework for health care
                                                                    antiseptic active ingredients (Ref. 11).
----------------------------------------------------------------------------------------------------------------

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. In
response to the 2013 Consumer Wash PR, we received safety data
regarding benzalkonium chloride that is relevant to this ingredient's
use in a consumer rub and these data are evaluated in section VIII.D.2.
Copies of the comments received are on public display at http://www.regulations.gov (see ADDRESSES). Because only consumer antiseptic
rubs are discussed in this proposed rule, only those comments and data
received in response to the 1994 TFM that are related to consumer
antiseptic rub 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 consumer antiseptic rub 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 data proposed in this proposed rule
as necessary to support a GRAS/GRAE determination. Comments that were
received in response to the 1994 TFM regarding other intended uses of
the active ingredients are addressed in the 2013 Consumer Wash PR (78
FR 76444), or the 2015 Health Care Antiseptic PR (80 FR 25166), 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 consumer antiseptic rub active ingredients (Ref. 12). We reviewed
the available literature and data and the comments submitted to the
rulemaking and are proposing that adequate data for a determination of
safety and effectiveness are not yet available for the consumer
antiseptic rub active ingredients.

IV. 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 consumer antiseptic rub 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) (Ref. 13).\2\ Conditions of use include, among other things,
active ingredient, dosage form and strength, route of administration,
and specific OTC use or indication of the product (see Sec.
330.14(a)). To determine eligibility for the OTC Drug Review, FDA
typically

must have actual product labeling or a facsimile of labeling that
documents the conditions of marketing of a product 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 consumer antiseptic rub does not affect eligibility under any other
OTC drug monograph.
---------------------------------------------------------------------------

    \2\ Also, note that drugs initially marketed in the United
States after the OTC Drug Review began in 1972 and drugs without any
U.S. marketing experience can be considered in the OTC monograph
system based on submission of a Time and Extent Application. (See
Sec.  330.14).
---------------------------------------------------------------------------

B. Eligibility of Certain Active Ingredients for the OTC Drug Review

    The following list includes those active ingredients that were
addressed in the 1994 TFM for use as an antiseptic hand wash or health
care personnel hand wash, and which currently do not have adequate
evidence of eligibility for evaluation under the OTC Drug Review for
use in a consumer antiseptic rub. Our review of the labeling submitted
to the Panel or to FDA at a later time did not identify evidence
demonstrating eligibility for the following active ingredients:

 Benzethonium chloride
 Chloroxylenol
 Chlorhexidine gluconate \3\
---------------------------------------------------------------------------

    \3\ Chlorhexidine gluconate 4 percent aqueous solution 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
topical antimicrobial monograph.
---------------------------------------------------------------------------

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

    Following the publication of the 1994 TFM, FDA received submissions
for the first time requesting that the following compounds be added to
the monograph (Refs. 14 through 20):

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

    These compounds were not addressed in prior FDA documents related
to the monograph and were not evaluated for antiseptic hand wash use by
the Antimicrobial I Panel. The submissions received by the Agency to
date do not include documentation demonstrating the eligibility of any
of these compounds for inclusion in the topical antimicrobial monograph
(Ref. 21). Because of their lack of eligibility, effectiveness and
safety information that has been submitted to the rulemaking for these
consumer antiseptic rub active ingredients are not discussed in this
proposed rule for such use. However, if documentation of the type
described in section IV.A is submitted, these active ingredients could
be determined to be eligible for evaluation for use as a consumer
antiseptic rub.

V. 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), 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.
None of these ingredients currently have adequate evidence of
eligibility for use in a consumer antiseptic rub (see section IV.B).
Consequently, effectiveness and safety information that has been
submitted to the rulemaking for these consumer antiseptic rub active
ingredients are not discussed in this proposed rule for such use.
However, if documentation of the type described in section IV.A is
submitted, these active ingredients could be determined to be eligible
for evaluation for use as a consumer antiseptic rub.

VI. Summary of Proposed Classifications of OTC Consumer Antiseptic Rub
Active Ingredients

    Table 3 lists the OTC consumer antiseptic active ingredients
eligible for evaluation under the OTC Drug Review for use in consumer
rubs, the classification proposed in the 1994 TFM, and the
classification being proposed in this rulemaking. For each active
ingredient, data that have been submitted to the public docket (for the
topical antimicrobial rulemaking) and evaluated by FDA and the
description of data still lacking in the administrative record are
described in detail in section VIII.

      Table 3--Classification of OTC Consumer Antiseptic Rub Active
          Ingredients in the 1994 TFM and in This Proposed Rule
------------------------------------------------------------------------
                                 1994 TFM proposal
       Active ingredient                \1\           This proposed rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent......  I \2\..............  IIISE \3\
Isopropyl alcohol 70 to 91.3    IIIE...............  IIISE
 percent.
Benzalkonium chloride.........  IIISE..............  IIISE
------------------------------------------------------------------------
\1\ Because the 1994 TFM did not describe antiseptic hand washes and
  rubs separately, the 1994 TFM classification was for use as an
  antiseptic hand wash or health care antiseptic hand wash.
\2\ ``I'' denotes a classification that an active ingredient has been
  shown to be safe and effective.
\3\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.

    In the 1994 TFM, alcohol was classified as Category I, isopropyl
alcohol was classified as Category IIIE, and benzalkonium chloride was
classified as Category IIISE for use as an antiseptic hand wash or
health care

personnel hand wash. However, in this proposed rule, we are proposing
to classify all three ingredients as Category IIISE for use as a
consumer antiseptic rub because additional effectiveness and safety
data are needed to classify each ingredient as GRAS/GRAE for this use.

VII. Effectiveness (Generally Recognized as Effective) Determination

    OTC regulations (Sec. Sec.  330.10(a)(4)(ii) and 314.126(b) (21 CFR
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 continued to apply a log reduction standard (a
clinical simulation standard) for establishing effectiveness of
consumer antiseptics originally proposed in the 1978 TFM (59 FR 31402
at 31412) 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). Although the test methods proposed in the 1994 TFM are
intended to evaluate the effectiveness of antiseptic final
formulations, this type of clinical simulation testing, when adequately
controlled, can also be used to demonstrate that an active ingredient
is GRAE for use in a consumer antiseptic rub product. As reflected by
the recommendations of some public health agencies, FDA believes that
consumer antiseptic rubs are generally used when hands are not visibly
soiled, and soap and water are not readily available (Refs. 22, 23),
for example, in settings such as school classrooms, childcare
facilities, outdoors and various other public places (Ref. 24).
However, as discussed in section VII.A, data from adequately controlled
studies demonstrating the impact of consumer antiseptic rubs on
infection rates are not available. In contrast to consumer washes, for
which we are asking for clinical outcome data to support the benefit of
these products, given the easily available alternative of washing with
soap and water, there is no similar readily available alternative for
consumer antiseptic rubs. A clinical outcome trial comparing the use of
consumer antiseptic rubs to standard hand washing with soap and water
has less applicability given that consumer antiseptic rubs are not
generally used in situations in which soap and water are a readily
available alternative. Therefore, we are currently recommending the use
of clinical simulation studies because they are a practical means to
assess the general effectiveness of consumer antiseptic rubs.
    FDA has already relied on clinical simulation studies as a standard
for evaluating effectiveness of hand antiseptic drug products approved
under NDAs, which are proven to be an effective measure to lower the
surgical site infection rate (Refs. 25 through 27). In addition, in our
recently revised standards for evaluating the effectiveness of health
care antiseptics published in May 2015 (80 FR 25166), we relied on
clinical simulation studies based on the recommendations of the March
2005 NDAC. In contrast, in the 2013 Consumer Wash PR, we proposed an
efficacy standard for consumer antiseptic washes that relies on
clinical outcome trials, also based on NDAC recommendations. As noted
previously, consumer antiseptic rub products are generally used when
soap and water are not available, so consumers lack a readily available
alternative. As such, we continue to propose a log reduction standard
to demonstrate the general recognition of effectiveness for consumer
antiseptic rubs in accordance with our standards for health care
antiseptics, which contain the same active ingredients (i.e., alcohol,
isopropyl alcohol, and benzalkonium chloride). Details of our current
proposed log reduction standard are outlined in section VII.B.
    As discussed in section VII.A, we have evaluated the available
effectiveness studies that were submitted to the OTC Drug Review or
retrieved through the published literature to support the effectiveness
for consumer antiseptic rubs using the log reduction criteria most
recently proposed in the 1994 TFM (59 FR 31402 at 31448) (Refs. 28 and
29). We found that the available studies are not adequate to support a
GRAE determination for any consumer antiseptic rub active ingredient
under either the final formulation effectiveness testing criteria
proposed in the 1994 TFM or under the GRAE criteria proposed in this
proposed rule (see table 4).
    We have also evaluated all the studies that were submitted to the
OTC Drug Review and have searched the published literature for studies
performed in consumer use settings that would provide the direct
evidence of a clinical benefit from the use of consumer antiseptic rubs
(Ref. 24). We are defining a clinical benefit here as a reduction in
the number of infections in a population that uses the consumer
antiseptic rubs. Although a definitive link between consumer antiseptic
rubs and reduced infection rates has not been established, some public
health agencies recommend the use of consumer antiseptic rubs when soap
and water are not available (Refs. 22, 23).

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
    Most of the available data to support the effectiveness of consumer
antiseptic rubs are based on clinical simulation studies, such as the
ones described in the 1994 TFM (59 FR 31402 at 31444). The premise
behind these studies as described in the 1994 TFM is that bacterial
reductions translate to a reduced risk for infection. However,
currently, there are no clinical data that demonstrate that the
specific bacterial log reductions that we have relied upon as a
demonstration of effectiveness lead to a specific reduction in
infections. In our view, although a lower number of bacteria on hands
may not directly translate into a reduced chance of infection, a
reduced bacterial load does decrease the opportunity for infection when
used in situations with no other options for hand cleansing. In this
case, rather than comparing using consumer antiseptic rubs to hand
washing with soap and water, we are comparing them to the alternative
of not cleaning the hands. In addition, because we believe that the
consumer antiseptic rubs are intended to provide immediate reduction of
bacteria rather than a persistent benefit, we are proposing that log
reductions be measured after a single bacterial challenge (see table
4), rather than after repeated contamination.
    We have evaluated all clinical simulation studies that were
submitted to the OTC Drug Review for evidence of the effectiveness of
consumer antiseptic rub active ingredients under the log reduction
criteria proposed in the 1994

TFM (59 FR 31402 at 31448) (Refs. 28 through 30). We also searched the
published literature for clinical simulation studies that assess
consumer antiseptic rubs' effectiveness using the log reduction
criteria in the 1994 TFM (Refs. 28 and 29).
    Overall, the studies used a variety of study designs, including
nonstandard study designs. In some cases, data submitted to the OTC
Drug Review were in the form of technical reports or published articles
without any study details. 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 at least one of the
following deficiencies:
     Some studies that were described as using a standardized
method (American Society for Testing and Materials (ASTM) \4\ 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.
---------------------------------------------------------------------------

    \4\ General information about ASTM can be found at https://www.astm.org/.
---------------------------------------------------------------------------

     Many studies did not include appropriate controls; for
example, most studies did not include a vehicle control or an active
control (59 FR 31402 at 31448), and some studies that included an
active control failed to use the control product according to its
labeled directions (59 FR 31402 at 31448).
     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 31449).
     Some studies did not sample all of the time points
specified by the test method (59 FR 31402 at 31448).
    FDA's detailed evaluation of the data is filed in Docket No. FDA-
2016-N-0124, available at http://www.regulations.gov.
2. Clinical Outcome Studies
    Although we are not currently proposing to require clinical outcome
studies to support a GRAE determination in this proposed rule, FDA
identified and evaluated clinical outcome studies from the published
literature that could potentially provide evidence of effectiveness for
the use of consumer antiseptic rubs (Ref. 24). In our view, clinical
outcome studies evaluating the effectiveness of consumer rubs should be
adequately controlled and include a placebo or negative control arm to
show the effect of an active ingredient. Among the reviewed studies and
published literature, there are only a few studies that use these
specified parameters for evaluating the effectiveness of consumer
antiseptic rubs (Ref. 25). Overall, most of the studies were
confounded, underpowered, and/or not properly controlled.
    Our detailed review of consumer hand rubs studies is available in
Docket No. FDA-2016-N-0124 (Ref. 24). None of the alcohol-based hand
rub studies demonstrating benefit were adequately controlled, thus they
could not demonstrate the contribution of the antiseptic active
ingredient to the observed clinical outcome of reduced infection rates.
In general, the studies had the following design flaws:
     No comparison to vehicle.
     Small sample size.
     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.
     Failure to observe and document hand rub application
technique.
    One clinical outcome study was identified that was randomized,
blinded, and placebo-controlled and was well designed to evaluate the
effectiveness of a particular antiseptic active ingredient (Ref. 31).
Although it had several significant limitations that prevent it from
being sufficient to establish effectiveness for use of the active
ingredient in a consumer antiseptic rub, this study is the best among
the available studies that evaluate the impact of consumer antiseptic
rubs on infections.
    This clinical outcome study performed in Sweden compared the
effectiveness of a 70-percent alcohol-containing consumer antiseptic
rub as an adjunct to hand washing with plain soap and water in
childcare centers (Ref. 31). The study included 60 childcare centers
(30 matched pairs) from 10 counties with a mean number of 50 children
in each center. One childcare center from each matched pair was
randomized to the intervention group, with the other serving as the
control group. The intervention groups were provided instructions
(verbal and written), and children and staff were asked to wash hands
with plain soap and water, then rub with a 70-percent alcohol-
containing consumer antiseptic rub. Control groups followed the same
hand-washing protocol without the hand rub. The primary outcome was the
rate of illness absenteeism. Parents were asked to report every episode
when the child was absent from childcare because of illness, including
the dates of absence, symptoms, and any medical treatment. There were
0.37 absences per 100 child hours in the control group, compared to
0.33 in the intervention group. The effect of the intervention was a
12-percent reduction in absenteeism. Based on the amount of hand rub
used during the study, the estimated frequency of hand rub use by each
child was two to six times per day. Although the study is well
designed, there are several significant limitations, such as the
following:
     No clinical or microbiological evaluation of illness.
     No specific infection was studied.
     Children kept home based on parent choice not addressed in
the statistical analysis.
     Degree of illness and symptoms to keep child home varied
among parents.

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 OTC consumer antiseptic rub products and that those reductions
are reflective of bacterial reductions that would be achieved during
use. For the use of antiseptic rubs, some public health agencies (Ref.
22) recommend their use when soap and water are not available, and when
there is no other reasonably available alternative for the consumer.
    In addition to the standards described in section VII.B, the
effectiveness of consumer antiseptic rubs can be affected by a variety
of other factors related to product formulation and use. Section VII.C
discusses these factors, which includes the number of times per day a

product is used and the volume used in each use.
1. In Vitro Studies
    The 1994 TFM proposed that the in vitro antimicrobial activity of
an active ingredient could be demonstrated 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. 32). 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.
33). Although we agree that the in vitro testing proposed in the 1994
TFM is not warranted for testing every final formulation of an
antiseptic product that contains a GRAE ingredient, we believe that a
GRAE determination for a consumer 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 GRAE status is a very broad determination 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 consumer antiseptic rub active ingredient
should be evaluated by the following testing:
     A determination of the in vitro spectrum of antimicrobial
activity against potential pathogens (listed in this section) that may
be encountered in consumer use settings where soap and water are not
readily available. MIC or MBC testing of 25 representative clinical
isolates and 25 reference (e.g., American Type Culture Collection
(ATCC)) strains of each of the microorganisms listed in this section.
     Time-kill testing of each of the following ATCC strains 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.
    Gram-negative organisms.
    [cir] Haemophilus influenzae.
    [cir] Bacteroides fragilis.
    [cir] Enterobacter species.
    [cir] Burkholderia cepacia (ATCC 25416 and ATCC 25608).
    [cir] Escherichia coli (ATCC 11775 and ATCC 25922).
    [cir] Klebsiella pneumoniae (ATCC 13883 and ATCC 27736).
    [cir] Pseudomonas aeruginosa (ATCC 15442 and ATCC 27853).
    [cir] Serratia marcescens (ATCC 8100 and ATCC 14756).
    [cir] Campylobacter jejuni (ATCC 33291 and ATCC 49943).
    [cir] Salmonella enterica Serovar Enteritidis (ATCC 13076) and
Serovar Typhimurium (ATCC 14028). Serovar refers to the subspecies
classification of a group of microorganisms based on cell surface
antigens.
    [cir] Shigella sonnei (ATCC 9290 and ATCC 25931).
    Gram-positive organisms.
    [cir] Enterococcus faecalis (ATCC 19433 and ATCC 29212).
    [cir] Staphylococcus aureus (ATCC 6538 and ATCC 29213) and
methicillin-resistant Staphylococcus aureus (ATCC 33591 and ATCC
33592).
    [cir] Streptococcus pyogenes (ATCC 14289 and ATCC 19615).
    [cir] Listeria monocytogenes (ATCC 7644 and ATCC 19115).
    [cir] Streptococcus pneumoniae (ATCC 6303 and ATCC 49619).
    We propose that a consumer antiseptic rub active ingredient be
considered bactericidal at the concentration and contact time that
demonstrates a 3-log10 (99.9 percent) or greater reduction
in bacterial viability for all the tested strains. This is the same
performance criterion used by the Clinical and Laboratory Standards
Institute (NCCLS, ``Methods for Determining Bactericidal Activity of
Antimicrobial Agents; Approved Guideline,'' NCCLS document M26-A,
1999).
    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 have not been
submitted to the rulemaking. Furthermore, published data may be
available that would satisfy some or all these data requirement. Data
from these in vitro studies, as well as data from the literature, may
be used to inform labeling, in particular, if there are specific
organisms for which an active ingredient does not have significant
activity. It is anticipated that if data supporting use of a consumer
antiseptic demonstrate lack of activity against a particular organism
that requires labeling, that labeling would also be relevant in the
health care setting.
2. In Vivo Studies
    Based on the recommendations of the March 2005 NDAC meeting for
health care antiseptic products, we continue to propose the use of
bacterial log reductions as a means of demonstrating that consumer
antiseptic rubs are GRAE (Ref. 8). The 1994 TFM also proposed final
formulation testing for antiseptic hand washes (59 FR 31402 at 31448).
We are not discussing the final formulation testing here because we are
not proposing that any of the ingredients are GRAS/GRAE. Although, as
previously noted, these proposed test methods are intended to evaluate
the effectiveness of antiseptic final formulations, this type of
clinical simulation testing when adequately controlled can also be used
to demonstrate that an active ingredient is GRAE for use in a consumer
antiseptic rub product. Based on our experience with the approval of
NDA antiseptic products, and input from the March 2005 and October 2005
NDAC meetings, we recommend that the bacterial log reduction studies
used to demonstrate that an active ingredient is GRAE for use in
consumer antiseptic rub 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 consumer antiseptic rub products. Products with vehicles that
have antimicrobial activity should consider using a negative control,
such as 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
test product, 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 neutralizer is used to
halt the antimicrobial activity of the antiseptic after product
exposure so that a continued effect through subsequent dilution steps
and culturing

thereby does not create inflated log reductions. 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
consumer antiseptic rubs, 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 31448). Our current criteria are laid out in table 4. We have
revised the log reduction criteria proposed for consumer antiseptic
rubs based on the recommendations of the March 2005 NDAC and comments
to the 1994 TFM, which argued that the demonstration of a cumulative
antiseptic effect for these products is unnecessary. We agree that the
critical element of the effectiveness is that a product must be
effective after the first application because that represents the way
in which consumer antiseptic rub products are used (59 FR 31402 at
31442). For these reasons, log reduction criteria are proposed only for
a single application of the test product rather than multiple
applications. Given that we are no longer requiring a cumulative
antiseptic effect, the log reduction criteria were revised to reflect
this single application and fall between the log reductions previously
proposed for the first and last applications. The GRAE criteria
proposed for consumer antiseptic rubs are based on log reductions
achieved by antiseptics as shown in the published literature (Refs. 28
and 29) as well as those evaluated under the NDA process. Table 4 shows
the log reductions that we would expect an effective consumer
antiseptic rub active ingredient to meet to show that it is GRAE.

      Table 4--Clinical Simulation Testing Bacterial Log Reduction
    Effectiveness Criteria in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
         Indication                 1994 TFM         This proposed rule
------------------------------------------------------------------------
Antiseptic hand wash/         (1) Reduction of 2    (1) Reduction of 2.5
 Consumer antiseptic rub.      log10 on each hand    log10 on each hand
                               within 5 minutes      within 5 minutes
                               after the first       after a single rub.
                               wash and
                              (2) Reduction of 3
                               log10 on each hand
                               within 5 minutes
                               after the tenth
                               wash.
------------------------------------------------------------------------

C. Impact of Application Parameters on Efficacy

    Establishing GRAE status of active ingredients is one important
aspect of ensuring the efficacy of OTC consumer antiseptic rub
products. The standards for a GRAE determination for consumer
antiseptic rubs have been described (see section VII.B). These
standards will help determine final monograph active ingredients, as
well as their permitted concentrations and the skin application time
needed for the active ingredient to achieve adequate bacterial
reduction. However, the efficacy of any particular final formulation of
a consumer antiseptic rub appears to be affected by a variety of other
factors related to product formulation and use.
    These factors include the number of times per day a product is used
and the volume used in each use. The number of times per day that a
consumer antiseptic rub product is applied has been shown to be
positively correlated with a reduction in illness-related absenteeism
in a kindergarten school (Ref. 34). In addition, more specific measures
of application parameters have been assessed. The volume of product
applied and the skin coverage achieved by the applied volume appear to
have an impact on efficacy of antiseptic rub products containing
alcohol. In comparing five different application volumes of 70 percent
ethanol gel with 85 percent ethanol gel and 70 percent ethanol foam,
Kampf et al. (2013) demonstrated that the label recommended volume of
1.1 milliliters (mL) for the 70 percent ethanol products was not
sufficient to achieve efficacy in in vivo efficacy testing according to
ASTM methods (Ref. 35). The recommended application of 2 mL of 85
percent gel, as well as higher than recommended volumes of the 70
percent products, met efficacy criteria under ASTM E 2755-10 and ASTM E
1174-06 methods used in this study. In the same study, insufficient
skin coverage with lower application volumes (1.1 mL) was suggested as
the reason for failure to achieve efficacy. Failure to achieve
effectiveness with the lower volume was based on observation of gaps in
skin coverage after volunteers applied products containing fluorescent
dye to their hands. In a similar study, Kampf (2008) assessed the
efficacy and coverage of four hand rub products (foam or gel
formulation unspecified) containing 85 percent, 62 percent, 61 percent,
or 60 percent ethanol (Ref. 36). At an application volume of 2.4 mL,
the 60 percent and 61 percent ethanol formulations failed to meet in
vivo ASTM efficacy criteria while 2.4 mL application volumes of 62
percent and 85 percent ethanol formulations met the criteria.
Application volumes of 3.6 mL met efficacy criteria for all ethanol
concentrations tested (Ref. 36).
    Given that the applied volume of product may have consequences for
product efficacy, the factors that may affect application volume are of
interest. Variability has been demonstrated in the output of both gel
and foam antiseptic rub dispensers. Macinga et al. (2013) measured
output from a single wall-mounted dispenser and among wall-dispensers
from different manufacturers (Ref. 37). In dispensing five different
gel formulations containing varying percentages of ethanol or
isopropanol, dispensers from five different manufacturers had outputs
that ranged from 0.9 to 1.3 mL per actuation. In dispensing three
different foam formulations each containing 70 percent ethanol, foam
dispensers from three different manufacturers ranged from 0.6 to 1.1 mL
per actuation. Furthermore, the volume of product that individuals
choose to apply may be affected, independent of labeled instruction, by
factors such as the time it takes hands to dry after application. Kampf
et al. (2010) assessed four foam formulations, each containing 62
percent ethanol, and found that the amount (weight) of foam applied was
significantly correlated with the perceived drying time (Ref. 38).
There is also evidence that final formulation affects efficacy.
Different products containing the same concentration of active
ingredient have been shown to perform differently when tested by in
vivo bacterial reduction testing (ASTM 1174) (Ref. 39). One ``novel''
gel formulation and one ``novel'' foam formulation, each

containing 70 percent ethanol, were both shown to be statistically
superior after both 1 and 10 applications compared to two marketed
formulations, one gel and one foam, both containing 70 percent ethanol.
All formulations were applied in equal volumes. The two ``novel''
formulations also demonstrated some evidence of improved performance
relative to a marketed gel containing 90 percent ethanol.
    Understanding the impact of product-related parameters, such as
formulation, dose applied, and application volume, to be used according
to the labeling is imperative. We also need to understand the extent to
which variability in product-related parameters must be reduced to
ensure that products achieve the results expected based on their use of
GRAE ingredients. Given the data demonstrating that efficacy varies
with dose, application volume, and formulation, final formulation
efficacy testing will be necessary for consumer antiseptic rub products
in order to confirm effectiveness and label the product appropriately
for use. However, because no ingredient has sufficient data to support
GRAS/GRAE status in this rulemaking, we are not proposing specific
final formulation testing or labeling at this time. Instead, we are
requesting data to allow the assessment of the impact of various
application parameters on efficacy and the interaction among them
(e.g., how does formulation affect application volume requirements) to
inform final formulation testing and labeling requirements.

VIII. Safety (Generally Recognized as Safe) Determination

    In the 1994 TFM, 11 active ingredients were proposed to be
classified as GRAS for antiseptic hand wash use, which includes 2
active ingredients (alcohol and isopropyl alcohol) that are eligible
for consumer antiseptic rub use (59 FR 31402 at 31435). As described in
section II.C, consumer antiseptic hand rubs were not addressed
separately from antiseptic hand washes in the 1994 TFM. There have
since been a number of important scientific developments affecting our
evaluation of the safety of the active ingredients in consumer
antiseptic rubs, 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. Furthermore,
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 consumer
antiseptic rub active ingredients. To fully address these new safety
concerns, additional safety data will be necessary to support a GRAS
determination for all consumer antiseptic rub active ingredients.
    Many of the safety considerations for consumer antiseptic rubs are
based on FDA's view that the use of consumer antiseptic rubs is a
``chronic'' use as that term is defined by the International Council on
Harmonisation (ICH).\5\ As defined by the ICH, 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). We
believe that consumer antiseptic rubs are often used on a daily basis
and sometimes repeatedly over the course of the day.
---------------------------------------------------------------------------

    \5\ FDA is a member of the ICH Steering Committee, the governing
body that oversees the harmonization activities, and contributes 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 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 consumer antiseptic use.
    Given the frequent repeated use of consumer antiseptic rubs,
systemic exposure may occur. Although some systemic exposure data exist
for all three consumer antiseptic rub active ingredients, data on
systemic absorption after maximal use are lacking. 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 and method, duration of exposure, product formulation, skin
condition, and age. Depending on the systemic absorption of the
ingredient, variability in absorption anticipated between formulations,
and the safety margin for toxic effects, final formulation safety
testing for particular ingredients may be needed to assure that
substantially different absorption that might significantly change the
margin of safety is not anticipated for a new formulation. FDA does not
address final formulation testing in this rulemaking because no
ingredients have been proposed as GRAS/GRAE. However, FDA recently
described final formulation safety testing for another class of OTC
dermal products regulated under the OTC drug monograph (Ref. 41).
    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 consumer antiseptic rub active
ingredients. Thus, we are continuing to propose that both animal and
human pharmacokinetic (PK) data are necessary for consumer antiseptic
rub 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 consumer antiseptic
active ingredients that has come to our attention since publication of
the 1994 TFM is data suggesting that some antiseptic active ingredients
have hormonal effects. Ingredients in topical antiseptic products can
cause alterations in the thyroid 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 through 56).
    Because consumer antiseptic rubs are used chronically and are
likely to be used by sensitive populations such as children and
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.

B. Antimicrobial Resistance

    In the 2013 Consumer Wash PR and 2015 Health Care Antiseptic PR,
FDA raised the concern of the development of antiseptic resistance and
its potential impact on the development of antibiotic resistance (78 FR
76444 at 76454 and 80 FR 25166 at 25180). This concern was based on
numerous reports of laboratory studies demonstrating the development of
reduced susceptibility to certain antiseptic active ingredients and
antibiotics after growth in nonlethal amounts of the antiseptic (i.e.,
low-to-moderate concentrations of antiseptic) and reports of the
persistence of low levels of some antiseptic active ingredients in the
environment (78 FR 76444 at 76454 and 80 FR 25166 at 25180). FDA
concluded in both of these proposed rules that, given the increasing
evidence of the magnitude of the antibiotic resistance problem and the
speed with which new antibiotic resistant organisms are emerging, it is
important to assess this potential consequence of antiseptic use and
requested data to address the concern (78 FR 76444 at 76454 and 80 FR
25166 at 25180). However, in its evaluation of the available data on
the development of resistance to alcohol and isopropyl alcohol in the
proposed rule for health care antiseptics, FDA cited a number of
factors (speed of action, multiple nonspecific toxic effects, and lack
of a residue) that made the development of resistance to these alcohols
as a result of health care antiseptic use unlikely. Based on these
factors, FDA concluded that no additional data relevant to this issue
were necessary to support a GRAS determination for these ingredients
for health care antiseptics (80 FR 25166 at 25184, 25187, and 25192).
Consistent with FDA's findings for alcohol and isopropyl alcohol in its
proposed rule for health care antiseptic, we have also tentatively
concluded that no further data on the development of resistance to
alcohol and isopropyl alcohol as a result of their use in consumer
antiseptic rub products are needed. This is not the case for
benzalkonium chloride for which additional laboratory studies will
assist in more clearly defining the potential for the development of
resistance. (See section VIII.D.2).

C. Studies To Support a Generally Recognized as Safe Determination

    A GRAS determination for consumer antiseptic rub active ingredients
must be supported by both nonclinical (animal) and clinical (human)
studies.\6\ To issue a final monograph for these products, this safety
data must be in the docket.\7\
---------------------------------------------------------------------------

    \6\ We encourage sponsors to consult with us on non-animal
testing methods they believe may be suitable, adequate, validated,
and feasible. We are willing to consider if alternative methods
could be assessed for equivalency to an animal test method.
    \7\ The Agency intends to consider only non-confidential
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
this data or information to the docket is set forth in this document
in the ADDRESSES section.
---------------------------------------------------------------------------

    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,
57 through 63). These guidance documents also provide relevant guidance
for performing the nonclinical studies necessary to determine GRAS
status for a consumer antiseptic rub active ingredient. Because
consumer antiseptic rubs may be used repeatedly and in sensitive
populations, we propose that consumer antiseptic rub 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, 57 through 63) provide a framework for the types of studies
that are needed for FDA to assess the safety of each consumer rub
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 consumer antiseptic rub active ingredients is provided in table 5.

           Table 5--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 of    Used as a surrogate to
 distribution, metabolism, and       administration.        the dose at which the       identify toxic systemic
 excretion (ADME) (Refs. 58 and                             toxic effects of an         exposure levels that can
 64).                                                       active ingredient are       then be correlated to
                                                            observed as a result of     potential human exposure
                                                            systemic exposure of the    via dermal
                                                            drug. ADME data provide:    pharmacokinetic study
                                                            The rate and extent an      findings. Adverse event
                                                            active ingredient is        data related to
                                                            absorbed into the body      particular doses and
                                                            (e.g., AUC, Cmax, Tmax)     drug levels (exposure)
                                                            \1\; where the active       in animals are used to
                                                            ingredient is distributed   help formulate a safety
                                                            in the body; whether        picture of the possible
                                                            metabolism of the active    risk to humans.
                                                            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)       Dermal administration  Helps determine how much    Used to relate the
 (Ref. 62).                          using multiple         of the active ingredient    potential human exposure
                                     formulations under     penetrates the skin,        to toxic drug levels
                                     maximum use            leading to measurable       identified in animal
                                     conditions.            systemic exposure.          studies.
Carcinogenicity (ICH S1A, S1B, and  Minimum of one oral    Provides a direct measure   Identifies the systemic
 S1C) (Refs. 40, 57, and 60).        and one dermal study   of the potential for        and dermal risks
                                     for topical products   active ingredients to       associated with drug
                                     \3\.                   cause tumor formation       active ingredients.
                                                            (tumorogenesis) in the      Taken together, these
                                                            exposed animals.            studies are used to
                                                                                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)     Oral administration..  Evaluates the effects of a
 (Ref. 59).                                                 drug on the developing
                                                            offspring throughout
                                                            gestation and postnatally
                                                            until sexual maturation.
Reproductive toxicity (ICH S5)      Oral administration..  Assesses the effects of a
 (Ref. 59).                                                 drug on the reproductive
                                                            competence of sexually
                                                            mature male and female
                                                            animals.
Hormonal effects (Ref. 63)........  Oral administration..  Assesses the drug's         Used in hazard assessment
                                                            potential to interfere      to determine whether the
                                                            with the endocrine 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.
\3\ Assessment of dermal carcinogenicity is considered important because the intended clinical route of
  administration of dermal, and skin exposure could be high. In addition, dermal exposure can result in systemic
  exposure to parent and metabolites that may differ from other routes. When substantial nonclinical information
  is already available for an active ingredient, the need for a dermal carcinogenicity study could be
  reconsidered based on available information such as negative systemic carcinogenicity information and lack of
  preneoplastic effects in chronic nonrodent dermal toxicity studies.

    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 September
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. This is particularly important for populations, such as
pregnant women (and fetuses), lactating women, and children, who may
have greater potential to experience deleterious developmental effects
from drug exposure. Human exposure data can then be compared to drug
levels in animals known to produce adverse effects in order to
calculate a safety margin.
    Based on input from the September 2014 NDAC meeting, the Agency has
also determined that results from a human 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. 62). 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 consumer 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, 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 per cohort should be
sufficient to get estimates of the PK parameters from a topically
applied consumer antiseptic.
    The MUsT should attempt to maximize the potential for drug
absorption to occur by considering the following design elements (Ref.
65):
     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 rub applications
during the study).
     Duration of dosing.

     Use of highest proposed strength (e.g., 95 percent
alcohol).
     Total involved surface area to be treated at one time
(e.g., hands).
     Amount applied per square centimeter.
     Method of application (e.g., rub).
     Sensitive and validated analytical methods.
    It also is important that the MUsT reflect maximal use conditions
of consumer antiseptic rubs using different formulations to fully
characterize the active ingredient's potential for dermal penetration.
There are very limited data on the maximal number of uses of antiseptic
rubs in consumer settings. Consumer antiseptic rubs used in
institutional settings, such as daycare centers, schools, and office
buildings, would be used (as per label directions) at higher rates than
in domestic households, and thus would represent maximal use. Kinnula
et al. (2009) surveyed workers in child daycare centers in Finland to
determine how commonly alcohol-containing hand rub gels were applied
daily (Ref. 66). The respondents (n = 128) reported applying the
alcohol hand rub gels up to 50 times per day. Using the upper limit of
applications per day of antiseptic hand rubs from this study, FDA is
considering 50 times per day as the maximal use of consumer hand rubs
in a consumer setting.
    It should be noted that a systemic carcinogenicity study will not
be required for an ingredient if a MUsT results in a steady state blood
level less than 0.5 nanograms (ng)/mL, and an adequately conducted
toxicology program demonstrates that there are no other signals for the
ingredient or any known structurally similar compound indicating the
potential for adverse effects at lower levels. The threshold value of
0.5 ng/mL is based on the principle that the level would approximate
the highest plasma level below which the carcinogenic risk of any
unknown compound would be less than 1 in 100,000 after a single dose.
    The lack of absorption in a MuST does not alleviate the need to
assess dermal carcinogenicity because the magnitude of exposure to the
skin can be much higher than would be covered by systemic studies. In
addition, systemic exposure to the parent compound and metabolites can
differ significantly for a dermally applied product because the skin
has metabolic capability and first-pass metabolism is bypassed via this
route of administration.
    To fulfill the maximum human exposure requirement, the MUsT study
should meet appropriate design standards using the highest
concentration sought under this proposed rule in formulations expected
to produce the highest in vivo absorption. The assay used in the MUsT
should be properly validated according to current Good Laboratory
Practices and consistent with FDA guidance for industry:
``Bioanalytical Method Validation'' (Ref. 67).
    We expect that the 0.5 ng/mL concentration will be sufficiently
above the assay's limit of quantitation-limit of detection to allow a
signal: Noise ratio that assures confidence in the derived
concentrations (in the case of ``exaggerated'' values) or lack of
concentrations.
3. Studies To Characterize Hormonal Effects
    We propose that data are also needed to assess whether consumer
antiseptic rub active ingredients have hormonal effects that could
produce developmental or reproductive toxicity. 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 consumer antiseptic rub 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.
     Exposure to antiseptic active ingredients may be long term
for some users.
    According to FDA's 2015 guidance on nonclinical evaluation of
endocrine-related drug toxicity (Ref. 63), endocrine effects may be
identified from the standard battery of toxicity tests conducted during
drug development and may not require additional separate studies.
4. Studies To Evaluate the Potential Impact of Antiseptic Active
Ingredients on the Development of Resistance
    Since the 1994 TFM published, the issue of antiseptic resistance
and whether bacteria that exhibit antiseptic resistance have the
potential for antibiotic cross-resistance has been the subject of much
study and scrutiny. One of the major mechanisms of antiseptic and
antibiotic cross-resistance is changes in bacterial efflux activity at
nonlethal concentrations of the antiseptic (Refs. 68 through 73).
Efflux pumps are an important nonspecific bacterial defense mechanism
that can confer resistance to a number of substances toxic to the cell,
including antibiotics (Refs. 74 and 75). The development of bacteria
that are resistant to antibiotics is an important public health issue,
and additional data may tell us whether use of antiseptics in consumer
settings may contribute to the selection of bacteria that are less
susceptible to both antiseptics and antibiotics. Therefore, we are
requesting additional data and information to address this issue for
ingredients other than alcohol or isopropyl alcohol (see section
VIII.D).
    FDA believes that a tiered approach is an efficient means of
developing data to address this issue. Laboratory studies in
conjunction with a literature review are a feasible first step in
evaluating the impact of exposure to nonlethal amounts of antiseptic
active ingredients on antiseptic and antibiotic bacterial
susceptibilities. However, only limited data exist on the effects of
antiseptic exposure on the bacteria that are predominant in the oral
cavity, gut, skin flora, and the environment (Ref. 76). These organisms
represent pools of resistance determinants that are potentially
transferable to human pathogens (Refs. 77 and 78). Thus, broader
laboratory testing of consumer antiseptic active ingredients would more
clearly define the scope of the impact of antiseptic active ingredients
on the development of antibiotic resistance and may be able to identify
those antiseptic active ingredients for which the development of
resistance is not a concern. Laboratory studies evaluating the
antiseptic and antibiotic susceptibilities of bacteria grown in the
presence of sublethal concentrations of antiseptic active ingredients
could help support a GRAS determination for antiseptic active
ingredients intended for use in OTC consumer antiseptic drug products.
The following types of organisms should be evaluated:
     Human bacterial pathogens.
     Nonpathogenic organisms, opportunistic pathogens, and
obligate anaerobic bacteria that make up the resident microflora of the
human skin, gut, and oral cavity.
     Food-related bacteria such as Listeria, Lactobacillus, and
Enterococcus.
     Nonpathogenic organisms and opportunistic pathogens from
relevant environmental sources (e.g., soil).

If the results of these studies show no evidence of changes in
antiseptic or antibiotic susceptibility, no further studies addressing
the development of resistance would be needed to support a GRAS
determination.
    For antiseptic active ingredients that demonstrate an effect on
antiseptic and

antibiotic susceptibilities, additional data will be necessary to help
assess the likelihood that similar effects would occur in the consumer
setting. Several types of data could be used to assess whether or not
ingredients with positive laboratory findings pose a public health
risk, and the type of data needed would depend on what is already known
about the antiseptic active ingredient's mechanism of action and
persistence in the environment. We do not anticipate that it will be
necessary to obtain data from multiple types of studies for each active
ingredient to adequately assess its potential to affect resistance.
Such types of data could include, but are not limited to, the
following:
     Information about the mechanism(s) of antiseptic action
(for example, membrane destabilization or inhibition of fatty acid
synthesis), and whether there is a change in the mechanism of action
with changes in antiseptic concentration.
     Information clarifying the bacteria's mechanism(s) for the
development of resistance or reduced susceptibility to the antiseptic
active ingredient (for example, efflux mechanisms).
     Data characterizing the potential for reduced antiseptic
susceptibility caused by the antiseptic active ingredient to be
transferred to other bacteria that are still sensitive to the
antiseptic.
     Data characterizing the concentrations and antimicrobial
activity of the antiseptic active ingredient in biological and
environmental compartments (for example, bacteria found on human skin,
in the gut, and in environmental matrices).
     Data characterizing the antiseptic and antibiotic
susceptibility levels of environmental isolates of bacteria in areas of
prevalent antiseptic use, such as in the home or in schools.

Data from the types of testing described previously, as well as from
testing of antiseptic and antibiotic susceptibilities of bacteria in
settings where consumer topical antiseptic rub use is prevalent can
help demonstrate whether or not changes in susceptibility are occurring
with actual use. Because actual use concentrations of consumer
antiseptics are much higher than the MICs for these active ingredients,
data from compartments where sublethal concentrations of biologically
active antiseptic active ingredients may occur (e.g., environmental
compartments) can give us a sense of the potential for change in
antimicrobial susceptibilities in these compartments (Refs. 79 through
81). FDA recognizes, however, that methods of evaluating this issue are
an evolving science and that there may be other data appropriate to
evaluate the impact of consumer antiseptic active ingredients on the
development of resistance. For this reason, FDA encourages interested
parties to consult with the Agency on the specific studies appropriate
to address this issue for a particular active ingredient.

D. Review of Available Data for Each Antiseptic Active Ingredient

    We have identified for each consumer antiseptic rub active
ingredient whether the studies outlined in section VIII.C are publicly
available. Table 6 lists the types of studies available for each
antiseptic active ingredient eligible for use as a consumer rub
proposed as Category I or Category III in the 1994 TFM and indicates
whether the currently available data are adequate to serve as the basis
of a GRAS determination. Although we have some data from submissions to
the rulemaking and from information we have identified in the
literature, our administrative record is incomplete for at least some
types of safety studies for each of the active ingredients (see table
6). As noted previously, only information that is part of the
administrative record for this rulemaking can form the basis of a GRAS/
GRAE determination.
    We recognize that data and information submitted in response to the
2013 Consumer Wash PR or 2015 Health Care Antiseptic PR may be relevant
to this proposed rule. At the time of publication of this proposed
rule, FDA's review of all submissions made to the 2015 Health Care
Antiseptic PR has not been completed. FDA requests that any information
relevant to consumer antiseptic rub active ingredients be resubmitted
under this docket (FDA-2016-N-0124).

                                Table 6--Safety Studies Available for Consumer Antiseptic Hand Rub Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                        Human            Animal                                                            Potential
        Active Ingredient          Pharmacokinetic  Pharmacokinetic        Oral            Dermal        Reproductive       Hormonal        Resistance
                                        (MUsT)           (ADME)      Carcinogenicity  Carcinogenicity  Toxicity (DART)      Effects         Potential
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol..........................           [cir]
Benzalkonium chloride............  ...............           [cir]            ...............                             [cir]
Isopropyl alcohol................           [cir]            [cir]   ...............           [cir]                     [cir]
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty cell indicates no data available; ``[cir]'' indicates incomplete data available; ``'' indicates available data are sufficient to make
  a GRAS/GRAE determination.

    In the remainder of this section, we discuss the existing data and
data gaps for alcohol, benzalkonium chloride and isopropyl alcohol, the
consumer antiseptic rub active ingredients that were proposed as GRAS
in the 1994 TFM, and explain why these active ingredients are no longer
proposed as GRAS for use in consumer antiseptic hand rubs (i.e., why
they are now proposed as Category III). We also discuss benzalkonium
chloride, which was proposed as Category III in the 1994 TFM and for
which there are some new data available and explain why this ingredient
is still Category III. These three ingredients are also used in health
care antiseptic products, and the safety data gaps identified in the
2015 Health Care Antiseptic PR are similar to those discussed in this
proposed rule for each ingredient. The requirements for a GRAS
determination for an ingredient are generally the same for either a
health care or consumer antiseptic product, with the exception of
higher maximal use for health care antiseptic products. Therefore, it
is anticipated that ingredients fulfilling the requirements for a
health care antiseptic GRAS determination would also meet the criteria
for GRAS as a consumer antiseptic, if eligible for that indication.
1. Alcohol
    In the 1994 TFM, FDA proposed to classify alcohol as GRAS for all
health care antiseptic uses based on the recommendation of the Advisory
Review Panel on OTC Miscellaneous External Drug Products (Miscellaneous
External Panel), which concluded that the topical application of
alcohol is safe (59 FR 31402 at 31412). In the 2013 Consumer Wash PR,
FDA proposed to separately evaluate the safety and effectiveness of the
OTC antiseptic drug products by use setting, specifically health care
and consumer antiseptic products. As defined in the 2013 Consumer Wash
PR, consumer

antiseptic products that are not rinsed off after use include hand rubs
and antiseptic wipes. FDA is proposing to classify alcohol as Category
III for use in consumer antiseptic rubs. Extensive studies have been
conducted to characterize the metabolic and toxic effects of alcohol in
animal models. Although the impetus for most of the studies has been to
study the effects of alcohol exposure via the oral route of
administration, some dermal toxicity studies are available and have
shown that, although there is alcohol absorption through human skin, it
is much lower than absorption via the oral route. Overall, there are
adequate safety data to make a GRAS determination for alcohol, with the
exception of human pharmacokinetic data under maximal use conditions.
    a. Summary of alcohol safety data.
    As discussed in more detail in the 2015 Health Care Antiseptic PR
(80 FR 25166 at 25185 to 25187), FDA has reviewed the following and
found them to be sufficient to characterize the safety of alcohol for
use in consumer antiseptic rubs:
     Animal ADME data demonstrating absorption of alcohol both
in vitro and in vivo (Refs. 82 through 86).
     Dermal and oral carcinogenicity data in animals and oral
carcinogenicity data in humans (Refs. 87 through 93).
     DART human data (Refs. 94 and 95).
     Data on the hormonal effects of alcohol in animals and
humans (Refs. 96 through 102).
     Data on the antimicrobial mechanism of alcohol (Refs. 103
through 106). Alcohol readily evaporates from the skin after topical
application, and the resulting lack of antiseptic residue on the skin
suggests that the topical application of alcohol is not likely to
contribute to the development of antimicrobial resistance (Refs. 103,
105).
    Alcohol human pharmacokinetic data. The 2015 Health Care Antiseptic
PR described data that characterize the level of dermal absorption and
expected systemic exposure in adults as a result of topical use of
alcohol-containing antiseptics (80 FR 25166 at 25185-25186). These data
do not cover maximal use of these products as detailed in section
VIII.D.1.a.
    A variety of alcohol-based hand rub product formulations and
alcohol concentrations have been used in these studies. Based on the
available data, which represents moderate hand rub use (7.5 to 40 hand
rub applications per hour, studied for 30 to 240 minutes), the highest
observed exposure was 1,500 milligrams (mg) of alcohol (Ref. 4), which
is the equivalent of 10 percent of an alcohol-containing drink. See
also the discussion of occupational exposure to alcohol via the dermal
route (Ref. 107) in the alcohol carcinogenicity section of the 2015
Health Care Antiseptic PR (80 FR 25166 at 25186).
    Although these data do indicate absorption of alcohol does occur
after topical administration of alcohol-containing antiseptic rubs, we
did not find the exposure conditions of these studies comparable to
exposure that are required by our current MUsT standards specified in
section VIII.C.2. Consequently, human pharmacokinetic data under
maximal use conditions as determined by a MUsT are needed to make a
GRAS determination for the alcohol-containing consumer antiseptic rubs.
    b. Alcohol safety data gap.
    In summary, our administrative record for the safety of alcohol is
incomplete with respect to the following:
     Human pharmacokinetic studies under maximal use conditions