60474 Federal Register/Vol. 82, No. 243/Wednesday, December 20

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60474 Federal Register / Vol. 82, No. 243 / Wednesday, December 20, 2017 / Rules and Regulations

DEPARTMENT OF HEALTH AND SUPPLEMENTARY INFORMATION: ingredients are benzalkonium chloride, benzethonium chloride, chloroxylenol, HUMAN SERVICES Table of Contents alcohol (also referred to as ethanol or Food and Drug Administration I. Executive Summary ethyl alcohol), isopropyl alcohol, and A. Purpose of the Final Rule povidone-iodine. Accordingly, FDA 21 CFR Part 310 B. Summary of the Major Provisions of the does not make a GRAS/GRAE Final Rule determination in this final rule for these [Docket No. FDA–2015–N–0101] C. Costs and Benefits six active ingredients for use as OTC RIN 0910–AH40 II. Table of Abbreviations and Acronyms health care antiseptics. The monograph Commonly Used in This Document or nonmonograph status of these six Safety and Effectiveness of Health III. Introduction A. Terminology Used in the OTC Drug ingredients will be addressed, either Care Antiseptics; Topical Antimicrobial Review Regulations after completion and analysis of ongoing Drug Products for Over-the-Counter B. Topical Antiseptics studies to address the safety and Human Use C. This Final Rule Covers Only Health Care effectiveness data gaps of these Antiseptics ingredients or at a later date, if these AGENCY: Food and Drug Administration, IV. Background studies are not completed. HHS. A. Significant Rulemakings Relevant to This rulemaking finalizes the ACTION: Final rule. This Final Rule nonmonograph status of the remaining B. Public Meetings Relevant to This Final 24 active ingredients intended for use in SUMMARY: The Food and Drug Rule health care antiseptics identified in the Administration (FDA, the Agency, or C. Scope of This Final Rule 2015 Health Care Antiseptic PR. No we) is issuing this final rule establishing D. Eligibility for the OTC Drug Review additional data were submitted to that certain active ingredients used in V. Comments on the Proposed Rule and FDA Response support monograph conditions for these nonprescription (also known as over- A. Introduction 24 health care antiseptic active the-counter or OTC) antiseptic products B. General Comments on the Proposed ingredients. Therefore, this rule intended for use by health care Rule and FDA Response finalizes the 2015 Health Care professionals in a hospital setting or C. Comments on Eligibility of Active Antiseptic PR and finds that 24 health other health care situations outside the Ingredients and FDA Response care antiseptic active ingredients are not hospital are not generally recognized as D. Comments on Effectiveness and FDA GRAS/GRAE for use as OTC health care safe and effective (GRAS/GRAE). FDA is Response antiseptics. Accordingly, OTC health issuing this final rule after considering E. Comments on Safety and FDA Response F. Comments on the Preliminary care antiseptic drugs containing any of the recommendations of the Regulatory Impact Analysis and FDA these 24 active ingredients are new Nonprescription Drugs Advisory Response drugs under section 201(p) of the Committee (NDAC); public comments VI. Ingredients Not Generally Recognized as Federal Food, Drug, and Cosmetic Act on the Agency’s notices of proposed Safe and Effective (FD&C Act) (21 U.S.C. 321(p)) for which rulemaking; and all data and VII. Compliance Date approved applications under section information on OTC health care VIII. Summary of Regulatory Impact Analysis 505 of the FD&C Act (21 U.S.C. 355) and antiseptic products that have come to A. Introduction part 314 (21 CFR 314) of the regulations the Agency’s attention. This final rule B. Summary of Costs and Benefits IX. Paperwork Reduction Act of 1995 are required for marketing and may be finalizes the 1994 tentative final X. Analysis of Environmental Impact misbranded under section 502 of the monograph (TFM) for OTC health care XI. Federalism FD&C Act (21 U.S.C. 352). antiseptic drug products that published XII. References This final rule covers only OTC health in the Federal Register of June 17, 1994 care antiseptics that are intended for use (the 1994 TFM) as amended by the I. Executive Summary by health care professionals in a proposed rule published in the Federal hospital setting or other health care Register (FR) of May 1, 2015 (2015 A. Purpose of the Final Rule situations outside the hospital. This Health Care Antiseptic Proposed Rule This final rule finalizes the 2015 final rule does not cover consumer (PR)). Health Care Antiseptic PR. This final rule applies to health care antiseptic antiseptic washes (78 FR 76444, 81 FR DATES: This rule is effective December products that are intended for use by 61106); consumer antiseptic rubs (81 FR 20, 2018. health care professionals in a hospital 42912); antiseptics identified as ‘‘first ADDRESSES: For access to the docket to setting or other health care situations aid antiseptics’’ in the 1991 First Aid read background documents or the outside the hospital. Health care tentative final monograph (TFM) (56 FR electronic and written/paper comments antiseptic products include health care 33644); or antiseptics used by the food received, go to https:// personnel hand washes, health care industry. www.regulations.gov and insert the personnel hand rubs, surgical hand B. Summary of the Major Provisions of docket number found in brackets in the scrubs, surgical hand rubs, and patient the Final Rule heading of this final rule, into the antiseptic skin preparations (i.e., patient ‘‘Search’’ box and follow the prompts, preoperative and preinjection skin 1. Safety and/or go to the Dockets Management preparations). Several important scientific Staff, 5630 Fishers Lane, Rm. 1061, In response to several requests developments that affect the safety Rockville, MD 20852. submitted to the 2015 Health Care evaluation of OTC health care antiseptic FOR FURTHER INFORMATION CONTACT: Antiseptic PR, FDA has deferred further active ingredients have occurred since Michelle M. Jackson, Center for Drug rulemaking on six active ingredients FDA’s 1994 safety evaluation. Improved Evaluation and Research, Food and used in OTC health care antiseptic analytical methods now exist that can Drug Administration, 10903 New products to allow for the development detect and more accurately measure Hampshire Ave., Bldg. 22, Rm. 5420, and submission to the record of new these active ingredients at lower levels Silver Spring, MD 20993–0002, 301– safety and effectiveness data for these in the bloodstream and tissue. 796–0923. ingredients. The deferred active Consequently, new data suggest that the

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systemic exposure to these active clinical practice, as well as input from 1972. To our knowledge, there is only ingredients is higher than previously the 2005 NDAC, prompted us to one ineligible product currently on the thought, and new information about the reevaluate the data needed to determine market, an alcohol-containing surgical potential risks from systemic absorption whether health care antiseptic active hand scrub, which is affected by this and long-term exposure is now ingredients are generally recognized as rule. available. New safety information also effective (GRAE). We continued to Benefits are quantified as the volume suggests that widespread antiseptic use propose the use of surrogate endpoints reduction in exposure to triclosan found could have an impact on the (bacterial log reductions) as a in health care antiseptic products development of bacterial resistance. To demonstration of effectiveness for affected by the rule, but these benefits support a classification of generally health care antiseptics combined with are not monetized. Annual benefits are recognized as safe (GRAS) for health in vitro testing to characterize the estimated to be a reduction in exposure care antiseptic active ingredients, we antimicrobial activity of the active of 88,000 kilograms (kg) of triclosan per proposed that additional data were ingredient (80 FR 25166). year. needed to demonstrate that those We have considered the Costs are calculated as the one-time ingredients meet current safety recommendations from the public costs associated with reformulating standards (80 FR 25166 at 25179 to meetings held by the Agency on health care antiseptic products 25195). antiseptics (see section IV.B, table 2) containing the active ingredient The minimum data needed to and evaluated the available literature, as triclosan and relabeling reformulated demonstrate safety for all health care well as the data, the comments, and products. We believe that the alcohol- antiseptic active ingredients fall into other information that were submitted containing surgical hand scrub that is four broad categories: (1) Human safety to the rulemaking on the effectiveness of affected by this rule is likely to be studies described in current FDA the 24 non-deferred health care removed from the market. We categorize guidance (e.g., maximal usage trial or antiseptic active ingredients addressed the associated loss of sales revenue as a ‘‘MUsT’’); (2) nonclinical safety studies in this final rule. Since the publication transfer from one manufacturer to described in current FDA guidance (e.g., of the 2015 Health Care Antiseptic PR, another and not a cost, because we developmental and reproductive no new data or information was assume that the supply of other, highly toxicity studies and carcinogenicity submitted on the effectiveness of these substitutable, products is highly elastic. studies); (3) data to characterize 24 non-deferred health care antiseptic Annualizing the one-time costs over a potential hormonal effects; and (4) data active ingredients. Consequently, there 10-year period, we estimate total to evaluate the development of is insufficient data to support a GRAE annualized costs to range from $1.1 to antimicrobial resistance. determination for these ingredients. $4.1 million at a 3 percent discount rate, We have considered the and from $1.2 to $4.7 million at a 7 C. Costs and Benefits recommendations from the public percent discount rate. The present value meetings held by the Agency on This rule establishes that 24 eligible of total costs ranges from $9.0 to $34.6 antiseptics (see section IV.B, table 2) active ingredients are not generally million at a 3 percent discount rate, and and evaluated the available literature, as recognized as safe and effective for use from $8.7 to $29.6 million at a 7 percent well as the data, the comments, and in nonprescription (also referred to as discount rate. other information that were submitted over-the-counter or OTC) health care In this final rule, small entities will to the rulemaking on the safety of the 24 antiseptics. However, data from the FDA bear costs to the extent that they must non-deferred health care antiseptic drug product registration database reformulate and re-label any health care active ingredients addressed in this final suggest that only one of these 24 antiseptic containing triclosan that they rule. The available information and ingredients is found in OTC health care produce. The average cost to small firms published data for these 24 active antiseptic products currently marketed of implementing the requirements of ingredients considered in this final rule pursuant to the TFM: Triclosan. this final rule is estimated to be are insufficient to establish the safety of Regulatory action is being deferred on $213,176 per firm. The costs of the these active ingredients for use in health six active ingredients that were changes, along with the small number of care antiseptic products. No additional included in the health care antiseptic firms affected, implies that this burden data were provided for these 24 proposed rule: Benzalkonium chloride, would not be significant, so we certify ingredients. Consequently, the available benzethonium chloride, chloroxylenol, that this final rule will not have a data do not support a GRAS ethyl alcohol, isopropyl alcohol, and significant economic impact on a determination for the OTC non-deferred povidone-iodine. This final rule also substantial number of small entities. health care antiseptic active ingredients addresses comments on the eligibility of This analysis, together with other addressed in this final rule. three active ingredients—alcohol (ethyl relevant sections of this document, alcohol), benzethonium chloride, and serves as the Regulatory Flexibility 2. Effectiveness chlorhexidine gluconate—and finds that Analysis, as required under the A determination that an active these three active ingredients are Regulatory Flexibility Act. ingredient is GRAS/GRAE for a ineligible for evaluation under the OTC The full discussion of economic particular intended use requires a Drug Review for certain health care impacts is available in docket FDA– benefit-to-risk assessment for the drug antiseptic uses because these active 2015–N–0101 and at https:// for that use. New information on ingredients were not included in health www.fda.gov/AboutFDA/ potential risks posed by the increased care antiseptic products marketed for ReportsManualsForms/Reports/ use of certain health care antiseptics in the specified indications prior to May EconomicAnalyses/default.htm.

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EXECUTIVE ORDER 13771 SUMMARY TABLE [In $ millions 2016 dollars, over an infinite time horizon]

Primary Lower bound Upper bound (7%) (7%) (7%)

Present Value of Costs ...... $17.19 $8.68 $29.47 Present Value of Cost Savings ...... Present Value of Net Costs ...... 17.19 8.68 29.47 Annualized Costs ...... 1.20 0.61 2.06 Annualized Cost Savings ...... Annualized Net Costs ...... 1.20 0.61 2.06

II. Table of Abbreviations and Acronyms Commonly Used in This Document

Abbreviation What it means

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

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Abbreviation What it means

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

III. Introduction testing is required). Section 330.10 by consumers for first aid use and In the following sections, we provide provides that any testing necessary to referred to them collectively as ‘‘first aid a brief description of terminology used resolve the safety or effectiveness issues antiseptics.’’ We published a separate in the OTC Drug Review regulations, an that resulted in an initial Category III TFM covering first aid antiseptics in the overview of OTC topical antiseptic drug classification, and submission to FDA of Federal Register of July 22, 1991 (56 FR products, and a more detailed the results of that testing or any other 33644). We do not discuss first aid description of the OTC health care data, must be done during the OTC drug antiseptics further in this document, antiseptic active ingredients that are the rulemaking process before the and this final rule does not have an subject of this final rule. establishment of a final monograph (i.e., impact on the status of first aid a final rule or regulation). Therefore, the antiseptics. A. Terminology Used in the OTC Drug proposed rules (at the tentative final The four remaining categories of Review Regulations monograph stage) used the concepts of topical antimicrobials were addressed in 1. Proposed, Tentative Final, and Final Categories I, II, and III. the 1994 TFM (59 FR 31402). The 1994 Monographs At this final monograph stage, FDA TFM covered: (1) Antiseptic hand wash To conform to terminology used in does not use the terms ‘‘Category I,’’ (i.e., consumer hand wash); (2) health the OTC Drug Review regulations ‘‘Category II,’’ and ‘‘Category III.’’ care personnel hand wash; (3) patient (§ 330.10 (21 CFR 330.10)), the advance Instead, the term ‘‘monograph preoperative skin preparation; and (4) notice of proposed rulemaking (ANPR) conditions’’ is used in place of Category surgical hand scrub (59 FR 31402 at that was published in the Federal I, and ‘‘nonmonograph conditions’’ is 31442). In the 1994 TFM, FDA also Register of September 13, 1974 (39 FR used in place of Categories II and III. identified a new category of antiseptics for use by the food industry and 33103) (the 1974 ANPR), was designated B. Topical Antiseptics as a ‘‘proposed monograph.’’ Similarly, requested relevant data and information the notices of proposed rulemaking, The OTC topical antimicrobial (59 FR 31402 at 31440). In section V.B.5, which were published in the Federal rulemaking has had a broad scope, we address comments filed in this Register of January 6, 1978 (43 FR 1210) encompassing drug products that may rulemaking on antiseptics for use by the (the 1978 TFM); the Federal Register of contain the same active ingredients, but food industry, but we do not otherwise June 17, 1994 (59 FR 31402) (the 1994 that are labeled and marketed for discuss these antiseptics in this TFM); and the Federal Register of May different intended uses. The 1974 ANPR document. This final rule does not have 1, 2015 (80 FR 25166) (the 2015 Health for topical antimicrobial products an impact on the status of antiseptics for Care Antiseptic PR), were each encompassed products for both health food industry use. designated as a TFM (see table 1 in care and consumer use (39 FR 33103). The 1994 TFM did not distinguish section IV.A). The 1974 ANPR covered seven different between consumer antiseptic washes intended uses for these products: (1) and rubs and health care antiseptic 2. Category I, II, and III Classifications Antimicrobial soap; (2) health care washes and rubs. In the 2013 Consumer The OTC drug regulations in § 330.10 personnel hand wash; (3) patient Wash PR, we proposed that our use the terms ‘‘Category I’’ (generally preoperative skin preparation; (4) skin evaluation of OTC antiseptic drug recognized as safe and effective and not antiseptic; (5) skin wound cleanser; (6) products be further subdivided into misbranded), ‘‘Category II’’ (not skin wound protectant; and (7) surgical health care antiseptics and consumer generally recognized as safe and hand scrub (39 FR 33103 at 33140). FDA antiseptics (78 FR 76444 at 76446). effective or misbranded), and ‘‘Category subsequently identified skin antiseptics, These categories are distinct based on III’’ (available data are insufficient to skin wound cleansers, and skin wound the proposed use setting, target classify as safe and effective, and further protectants as antiseptics used primarily population, and the fact that each

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setting presents a different level of risk (i.e., preinjection), may be used by hand rubs, surgical hand rubs, and for infection. In the 2013 Consumer patients outside the traditional health patient antiseptic skin preparations. Wash PR (78 FR 76444 at 76446 to care setting. Some patients (e.g., Completion of the monograph for 76447) and the 2016 Consumer Rub PR diabetics who manage their disease with health care antiseptic products and (81 FR 42912 at 42915 to 42916), we insulin injections) self-inject certain other monographs for the active proposed that our evaluation of OTC medications that have been prescribed ingredient triclosan is subject to a consumer antiseptic drug products be by a health care professional for use at Consent Decree entered by the U.S. further subdivided into consumer home or at other locations and use District Court for the Southern District washes (products that are rinsed off patient preoperative skin preparations of New York on November 21, 2013, in with water, including hand washes and prior to injection. Natural Resources Defense Council, Inc. body washes) and consumer rubs In this final rule, we use the term v. United States Food and Drug (products that are not rinsed off after ‘‘health care antiseptics’’ to include the Administration, et al., 10 Civ. 5690 use, including hand rubs and following products: (S.D.N.Y.). antibacterial wipes). This final rule does • Health care personnel hand washes • not have an impact on the status of Health care personnel hand rubs IV. Background • Surgical hand scrubs consumer antiseptic wash or consumer • In this section, we describe the antiseptic rub products. Surgical hand rubs • Patient antiseptic skin preparations significant rulemakings and public C. This Final Rule Covers Only Health (i.e., patient preoperative and meetings relevant to this rulemaking Care Antiseptics preinjection skin preparations) 1 and discuss our response to comments This final rule covers health care received on the 2015 Health Care We refer to the group of products antiseptic products that are rubs and Antiseptic PR. covered by this final rule as ‘‘health care others that are washes. The 1994 TFM A. Significant Rulemakings Relevant to antiseptics.’’ Health care antiseptics are did not distinguish between products This Final Rule drug products that are generally that we are now calling health care intended for use by health care ‘‘antiseptic washes’’ and products we A summary of the significant Federal professionals in a hospital setting or are now calling health care ‘‘antiseptic Register publications relevant to this other health care situations outside the rubs.’’ Washes are rinsed off with water, final rule is provided in table 1. Other hospital. Patient antiseptic skin and include health care personnel hand publications relevant to this final rule preparations, which are products that washes and surgical hand scrubs. Rubs are available at https:// are used for preparation of the skin prior are sometimes referred to as ‘‘leave-on www.regulations.gov in FDA Docket No. to surgery (i.e., preoperative) and products’’ and are not rinsed off after 1975–N–0012 (formerly Docket No. preparation of skin prior to an injection use. Rubs include health care personnel 1975–N–0183H).

TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO HEALTH CARE ANTISEPTIC DRUG PRODUCTS 1

Federal Register notice Information in notice

1974 ANPR (September 13, 1974, We published an ANPR to establish a monograph for OTC topical antimicrobial drug products, together 39 FR 33103). with the recommendations of the advisory review panel (the Panel) responsible for evaluating data on the active ingredients in this drug class. 1978 Antimicrobial TFM (January 6, We published our tentative conclusions and proposed effectiveness testing for the drug product categories 1978, 43 FR 1210). evaluated by the Panel, reflecting our evaluation of the Panel’s recommendations and comments and data submitted in response to the Panel’s recommendations. 1991 First Aid TFM (July 22, 1991, We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic products. In the 56 FR 33644). 1991 TFM, we proposed that first aid antiseptic drug products be indicated for the prevention of skin infections in minor cuts, scrapes, and burns. 1994 Healthcare Antiseptic TFM We amended the 1978 TFM to establish a separate monograph for the group of products referred to as (June 17, 1994, 59 FR 31402). OTC topical health care antiseptic drug products. These antiseptics are generally intended for use by health care professionals. In the 1994 TFM, we also recognized the need for antibacterial personal cleansing products for consumers to help prevent cross-contamination from one person to another and proposed a new antiseptic category for consumer use: Antiseptic hand wash. 2013 Consumer Antiseptic Wash We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining TFM (December 17, 2013, 78 FR whether OTC consumer antiseptic washes are GRAS/GRAE. 76444). In the 2013 Consumer Antiseptic Wash TFM, we proposed that additional safety and effectiveness data are necessary to support the safety and effectiveness of consumer antiseptic wash active ingredients. 2015 Health Care Antiseptic TFM We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining (May 1, 2015, 80 FR 25166). whether OTC health care antiseptics are GRAS/GRAE. In the 2015 Health Care Antiseptic TFM, we proposed that additional data are necessary to support the safety and effectiveness of health care antiseptic active ingredients. 2016 Consumer Antiseptic Rub We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining TFM (June 30, 2016, 81 FR whether OTC consumer antiseptic rubs are GRAS/GRAE. 42912). In the 2016 Consumer Antiseptic Rub TFM, we proposed that additional safety and effectiveness data are necessary to support the safety and effectiveness of consumer antiseptic rub active ingredients.

1 Because the category of products referred to as encompasses products that are used for preinjection refer to such products as ‘‘patient antiseptic skin ‘‘patient preoperative skin preparations’’ in the skin preparation in health care settings outside the preparations.’’ 1994 TFM and the 2015 Health Care Antiseptic PR hospital (so not preoperative), in this final rule we

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TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO HEALTH CARE ANTISEPTIC DRUG PRODUCTS 1— Continued

Federal Register notice Information in notice

2016 Consumer Antiseptic Wash We issued a final rule finding that certain active ingredients used in OTC consumer antiseptic wash prod- Final Monograph (September 6, ucts are not GRAS/GRAE. 2016, 81 FR 61106). We deferred further rulemaking on three specific active ingredients (benzalkonium chloride, benzethonium chloride, and chloroxylenol) used in OTC consumer antiseptic wash products to allow for the development and submission of new safety and effectiveness data to the record for those ingredients. 1 The publications listed in table 1 can be found at FDA’s ‘‘Status of OTC Rulemakings’’ website available at http://www.fda.gov/Drugs/Develop- mentApprovalProcess/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 In addition to the Federal Register care antiseptic safety and effectiveness. Final Rule publications listed in table 1, there have These meetings are summarized in table been three meetings of the NDAC that 2. are relevant to the discussion of health

TABLE 2—PUBLIC MEETINGS RELEVANT TO HEALTH CARE ANTISEPTICS

Date and type of meeting Topic of discussion

January 1997, NDAC Meeting (Joint meeting with the Anti-Infective Antiseptic and antibiotic resistance in relation to an industry proposal Drugs Advisory Committee) (January 6, 1997, 62 FR 764). for consumer and health care antiseptic effectiveness testing (Health Care Continuum Model) (Refs. 1 and 2). 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. 3). September 2014, NDAC Meeting (July 29, 2014, 79 FR 44042) ...... Safety testing framework for health care antiseptic active ingredients (Ref. 4).

C. Scope of This Final Rule ingredients are not included in the OTC indication of the product (see topical antiseptic monograph at this This rulemaking finalizes the § 330.14(a)). To determine eligibility for time. Products containing these nonmonograph status of the 24 listed the OTC Drug Review, FDA typically ingredients are new drugs for which health care antiseptic active ingredients must have actual product labeling or a approved new drug applications (NDAs) (see section IV.D.1). Requests were facsimile of labeling that documents the or abbreviated new drug applications made that benzalkonium chloride, conditions of marketing of a product (ANDAs) are required prior to benzethonium chloride, chloroxylenol, before May 1972 (see § 330.10(a)(2)). marketing. Accordingly, FDA is alcohol, isopropyl alcohol, and FDA considers a drug that is ineligible amending part 310 (21 CFR part 310) to povidone-iodine be deferred from for inclusion in the OTC monograph add the active ingredients covered by consideration in this health care system to be a new drug that requires this final rule to the list of active antiseptic final rule to allow more time FDA approval of an NDA or ANDA. ingredients in § 310.545 (21 CFR for interested parties to complete the Ineligibility for use as a health care 310.545) that are not GRAS/GRAE for studies necessary to fill the safety and antiseptic does not affect eligibility use in the specified OTC drug products. effectiveness data gaps identified in the under any other OTC drug monograph. 2015 Health Care Antiseptic PR for D. Eligibility for the OTC Drug Review 1. Eligible Active Ingredients these ingredients. In January 2017, we An OTC drug is covered by the OTC agreed to defer rulemaking on these six Drug Review if its conditions of use Table 3 lists the health care antiseptic ingredients (see Docket No. 2015–N– existed in the OTC drug marketplace on active ingredients that have been 0101 at https://www.regulations.gov). or before May 11, 1972 (37 FR 9464) considered under this rulemaking and For the 24 active ingredients included (Ref. 5).2 Conditions of use include, shows whether each ingredient is in this final rule, no additional data among other things, active ingredient, eligible or ineligible for evaluation were submitted to the record to fill the dosage form and strength, route of under the OTC Drug Review for use in safety and effectiveness data gaps administration, and specific OTC use or health care antiseptics for each of the identified in the 2015 Health Care 2 Also, note that drugs initially marketed in the five specified uses: Patient antiseptic Antiseptic PR for these 24 active United States after the OTC Drug Review began in skin preparation, health care personnel ingredients. Therefore, we find that 1972 and drugs without any U.S. marketing hand wash, health care personnel hand these 24 active ingredients are not experience can be considered in the OTC rub, surgical hand scrub, and surgical GRAS/GRAE for use in health care monograph system based on submission of a time and extent application. (See § 330.14.) hand rub. antiseptic drug products and these

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TABLE 3—ELIGIBILITY OF ANTISEPTIC ACTIVE INGREDIENTS FOR HEALTH CARE ANTISEPTIC USES 1

Patient antiseptic Health care Health care Surgical Surgical Active ingredient skin personnel personnel hand scrub hand rub preparation hand wash hand rub

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

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

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evaluation under the OTC Drug Review help distinguish among the different these studies are not completed. We did for use as a health care antiseptic for the comments. We have grouped similar not receive any deferral requests for the specified indications (see table 3). comments together under the same 24 remaining health care antiseptic Consequently, we find that these active number, and in some cases, we have active ingredients, and so we decline to ingredients continue to be ineligible for separated different issues discussed in defer final action on the proposed rule evaluation under the OTC Drug Review the same comment and designated them for these ingredients. for use as a health care antiseptic for the as distinct comments for purposes of 2. Use in Health Care Settings Outside specified indications and drug products our responses. The number assigned to the Hospital containing these ineligible active each comment or comment topic is ingredients will require approval under purely for organizational purposes and (Comment 2) One comment requested an NDA or ANDA prior to marketing. does not signify the comment’s value, that FDA ‘‘better clarify and define the importance, or the order in which scope’’ of this rulemaking on the use of 3. Ingredients Previously Proposed as comments were received. health care antiseptics in health care Not Generally Recognized as Safe and settings outside of the hospital ‘‘in order Effective B. General Comments on the Proposed that the proper antiseptic products are FDA may determine that an active Rule and FDA Response provided for patients in the spectrum of ingredient is not GRAS/GRAE for a 1. Effective Date health care settings while also being given OTC use (i.e., nonmonograph) covered by health care insurers.’’ The (Comment 1) Several comments comment stated that patients and health because of lack of evidence of requested that FDA extend its timeline effectiveness, lack of evidence of safety, care workers in these other settings under the 2015 Health Care Antiseptic deserve the same level of safety and or both. In the 1994 TFM (59 FR 31402 PR to allow more time for the at 31435 to 31436) and the 2015 Health efficacy standards as those in the submission of new data and hospital setting. The comment Care Antiseptic PR (80 FR 25166 at information. They asserted that the one 25173 to 25174), FDA proposed that the expressed concern that certain entities year compliance date was too short and may determine that they need to supply active ingredients fluorosalan, that it could take several years to design, hexachlorophene, phenol (greater than products intended for ‘‘consumer use,’’ execute, analyze, and report on the which, the comment stated, may have 1.5 percent), and tribromsalan be found necessary safety and effectiveness not GRAS/GRAE for the uses set forth in different and lesser standards. studies. (Response 2) We agree that health care the 1994 TFM: Antiseptic hand wash, (Response 1) In the 2015 Health Care health care personnel hand wash, antiseptic products are used in a variety Antiseptic PR, we provided a process of health care settings, not just patient antiseptic skin preparation, and for seeking an extension of time to surgical hand scrub. FDA did not hospitals. Over the past several decades, submit the required safety and there has been a significant shift in classify hexachlorophene or effectiveness data if such an extension tribromsalan in the 1978 TFM (43 FR health care delivery from the acute, is necessary (80 FR 25166 at 25169). As inpatient hospital setting to a variety of 1210 at 1227) because it had already explained in the proposed rule, we taken final regulatory action against outpatient and community-based stated that we would consider all the settings. There are many examples of hexachlorophene (21 CFR 250.250) and data and information submitted to the certain halogenated salicylamides, health care settings outside the hospital record in conjunction with all timely that involve the use of antiseptic notably tribromsalan (21 CFR 310.502). and completed requests to extend the No substantive comments or new data products. These settings include, but are timeline to finalize the monograph not limited to, the care of patients in were submitted to the record of the 1994 status for a given ingredient. We TFM or the 2015 Health Care Antiseptic outpatient medical and surgical received requests to defer six health care facilities, dental clinics, skilled nursing PR to support reclassification of any of antiseptic active ingredients from this these ingredients as GRAS/GRAE. facilities or nursing homes, adult rulemaking. Consideration for deferral medical day care centers, public health Therefore, FDA has determined that for an ingredient was given to requests these active ingredients are not GRAS/ clinics, imaging centers, oncology with clear statements of intent to clinics, infusion centers, dialysis GRAE for use in OTC health care conduct the necessary studies required antiseptic products as defined in this centers, behavioral health clinics, to fill all the data gaps identified in the physical therapy and rehabilitation final rule, and drug products containing proposed rule for that ingredient. After these ineligible active ingredients will centers, and in private homes. The term analyzing the data and information ‘‘health care’’ as used in this rulemaking require approval under an NDA or submitted related to the requests for ANDA prior to marketing. includes all these settings. extensions, we determined that a We note, however, that this rule does V. Comments on the Proposed Rule and deferral is warranted for the six health not address the use of a specific health FDA Response care antiseptic active ingredients— care antiseptic drug product in a benzalkonium chloride, benzethonium particular health care situation. In A. Introduction chloride, chloroxylenol, alcohol, addition, the coverage of antiseptic drug In response to the 2015 Health Care isopropyl alcohol, and povidone- products by health care insurers is Antiseptic PR, we received iodine—to allow more time for outside FDA’s purview. approximately 29 comments from drug interested parties to complete the manufacturers, trade associations, studies necessary to fill the safety and 3. GRAS/GRAE Classification of Certain academia, testing laboratories, health effectiveness data gaps identified for Ingredients professionals, and individuals. We also these ingredients in the 2015 Health (Comment 3) Several comments received additional data and Care Antiseptic PR. The monograph requested that FDA reconsider its information for certain deferred health status of these six ingredients will be proposal in the 2015 Health Care care antiseptic active ingredients. addressed either after completion and Antiseptic PR to classify alcohol, We describe and respond to the analysis of ongoing studies to address isopropyl alcohol, and povidone-iodine comments in section V.B through V.F. the safety and effectiveness data gaps of as Category III active ingredients. In the We have numbered each comment to these ingredients or at a later date if 1994 TFM, alcohol, isopropyl alcohol,

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and povidone-iodine were proposed to enough data on these three ingredients alcohol, isopropyl alcohol, and be classified as Category I topical to meet our proposed safety and povidone-iodine from Category I to antiseptic ingredients for certain effectiveness data requirements. We Category III, indicating that this change indications. The comments contended explained that we were proposing in the proposed classification could lead that FDA’s proposal to change these changes to the safety and effectiveness health care personnel to stop using ingredients’ proposed classification data requirements identified in the 1994 products with these active ingredients. from Category I to Category III is not TFM in light of comments we received, At the same meeting, FDA emphasized based on a safety or effectiveness input from subsequent public meetings, both that health care antiseptics are a concern or issue. One comment noted and our independent evaluation of other critically important part of the infection that during the September 3, 2014, relevant scientific information (80 FR control paradigm in place in every NDAC meeting, several NDAC members 25166 at 25166). hospital across the country and that our expressed concerns about changing the Among other things, our proposed goal is not to remove such products proposed classification of alcohol, revisions to the data requirements from the market (Ref. 4). That remains isopropyl alcohol, and povidone-iodine identified in the 1994 TFM were based our goal, and we note that these from Category I to Category III, on several important scientific ingredients have each been deferred, so indicating that the change in the developments that affected the safety they are not addressed in this final rule. proposed classification could lead evaluation of health care antiseptic 4. Patient Preoperative Skin Preparation health care personnel to stop using active ingredients, including improved products with these active ingredients. analytical methods that can detect and (Comment 4) One comment asked The comment also pointed out that, in more accurately measure these FDA to clarify the term ‘‘patient the 2015 Health Care Antiseptic PR and ingredients at lower levels in the preoperative skin preparation,’’ noting in related public announcements, FDA bloodstream and tissue (80 FR 25166 at that, in the 2015 Health Care Antiseptic emphasized that we did not believe that 25166 to 25167). As a result of these PR, the term ‘‘patient preoperative skin health care antiseptic products improved methods, we have learned preparation’’ includes skin preparation containing these ingredients were that some systemic exposures can be prior to an injection (preinjection) and ineffective or unsafe, or that their use detected, where previously they were that this may cause confusion because it should be discontinued. In fact, that undetected, and that some systemic could be misinterpreted to mean that all comment noted that FDA recommended exposures are higher than previously products listed can be used for either that health care personnel continue to thought. We also have new information patient preoperative skin preparation or use these antiseptic products consistent about the potential risks from systemic preinjection. with infection control guidelines while absorption and long-term exposure (80 Several comments also asserted that additional data about the products were FR 25166 at 25167). In addition, the the effectiveness testing for preinjection gathered. standard battery of tests that were used should have different clinically relevant (Response 3) As we explained in the to determine the safety of drugs had time points because preinjection use 2015 Heath Care Antiseptic PR, the OTC changed over time to incorporate serves a different purpose and has a drug procedural regulations in § 330.10 improvements in safety testing. As we different use pattern than patient use the terms ‘‘Category I’’ (generally explained in the 2015 Health Care preoperative skin preparations. They recognized as safe and effective and not Antiseptic PR, it is critical that the argued that surgical incision demands misbranded), ‘‘Category II’’ (not safety and effectiveness of these persistent activity due to the invasive generally recognized as safe and ingredients be supported by data that nature of cutting through the skin’s effective or misbranded), and ‘‘Category meet the most current standards, natural barrier over a larger area, the III’’ (available data are insufficient to considering the prevalent use of health procedure duration (which can be classify as safe and effective, and further care antiseptic products (80 FR 25166 at hours), and the time the incision point testing is required) (80 FR 25166 at 25167). will be open and will subsequently need 25168). We classify ingredients as Our decision to propose revising the to heal. As such, the comments argued, Category I, II, or III until the final safety and effectiveness data persistence may be an important monograph stage, at which point we use requirements identified in the 1994 attribute of patient preoperative skin the term ‘‘monograph conditions’’ in TFM was also based in part on meetings preparations. They explained that in place of Category I, and the term of the NDAC that were held in March contrast, an injection is a procedure ‘‘nonmonograph conditions’’ in place of 2005 and September 2014. As we noted lasting only seconds and poses a Categories II and III. In the 1994 TFM, in the preamble to the 2015 Health Care relatively low risk of infection. They alcohol and povidone-iodine were both Antiseptic PR, input from participants also explained that the injection site proposed to be classified as Category I at the March 2005 NDAC meeting heals quickly, so there is no need for topical antiseptic ingredients for use in prompted us to reevaluate the data persistent antimicrobial activity. They surgical hand scrubs, patient antiseptic needed for classifying health care stated that if patient preinjection skin skin preparations, and antiseptic hand antiseptic active ingredients as GRAE preparation products are required to washes or health care personnel hand (80 FR 25166 at 25166). Moreover, at the meet the same effectiveness wash products (59 FR 31402 at 31420 meeting held in September 2014, the requirements as patient preoperative and 31433). Isopropyl alcohol was NDAC discussed FDA’s proposed skin preparation products, this would proposed to be classified as Category I revisions to the safety data requirements effectively clear the market of available for patient antiseptic skin preparation and unanimously voted that the revised cost effective solutions for those who ‘‘for the preparation of the skin prior to safety data requirements were need these products. Therefore, the an injection’’ (59 FR 31402 at 31433). appropriate to demonstrate that a health comments asserted that the effectiveness In the 2015 Health Care Antiseptic care antiseptic active ingredient is requirements for patient preoperative PR, we changed the proposed GRAS. skin preparation should be different classification of alcohol, isopropyl As one comment noted, at the from the effectiveness requirements for alcohol, and povidone-iodine from September 2014 meeting, several NDAC patient preinjection skin preparations. Category I to III for these indications, members expressed concerns about (Response 4) We agree that the because we found that there was not changing the proposed classification of circumstances under which health care

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antiseptics can be used for preinjection bacterial reductions achieved using tests C. Comments on Eligibility of Active should be clarified because patient that simulate conditions of actual use Ingredients and FDA Response preoperative skin preparations and for each OTC health care antiseptic 1. Benzethonium Chloride preinjection skin preparations can serve product reflect the bacterial reductions different purposes and have different that would be achieved under (Comment 6) In response to the 2015 uses. Accordingly, we clarify that conditions of such use. Thus, the Health Care Antiseptic PR, we received patient preoperative skin preparation effectiveness requirements for a comment asserting that benzethonium and patient preinjection skin determining whether an active chloride is eligible for review under the preparation may involve separate uses ingredient is GRAE for use in patient monograph for use in health care within the category of patient antiseptic preinjection skin preparations should be personnel hand rubs and surgical hand skin preparations. As noted in the consistent with the actual use of that rubs and that benzethonium chloride be comments, surgical incisions require product. We agree that patient antiseptic categorized as a Category I ingredient for persistent activity from patient skin preparations used for preinjection both indications. Information submitted preoperative skin preparations due to involve a process lasting a much shorter in the comment showed that methylbenzethonium chloride was the invasive nature of cutting through period of time, sometime seconds, present in Bactine, a topical antiseptic the skin’s natural barrier over a larger compared to surgery, which can last for first aid and wound care before May area, the procedure duration (which can several hours, and that such 1972. The comment also asserted that: be hours), and the time the incision preinjection use has a lower risk of • point will be open and will Methylbenzethonium chloride was infection. For these reasons, we also the active ingredient in the antiseptic, subsequently need to heal. As such, agree that the effectiveness requirements persistence is an important attribute of Bactine. for preinjection should be different than • Bactine with methylbenzethonium patient preoperative skin preparations. the effectiveness requirements for chloride was in use before 1972 as a In comparison, injection refers to a brief patient preoperative skin preparations. leave-on antiseptic (not rinsed off). interruption of skin integrity by a sterile We discuss these effectiveness • Methylbenzethonium chloride and needle that is typically removed within requirements in more detail in section benzethonium chloride are equivalent. seconds or a few minutes. Due to the V.D.2. • The conditions of use for brevity of the procedure, the risk of benzethonium chloride in the 2015 bacterial infection from an injection is We also note that, although we do not address labeling in this final rule Health Care Antiseptic PR are the same low, and so persistent antimicrobial as for Bactine. activity is not essential for a because at this time we have not found any active ingredients to be GRAS/ (Response 6) In the 2015 Health Care preinjection skin preparation product. Antiseptic PR (80 FR 25166 at 25171), Examples of procedures that are GRAE for use in patient antiseptic skin preparations, we anticipate that labeling we explained that an OTC drug is covered by a preinjection claim include covered by the OTC Drug Review if its the following: for these products will include directions for use that will help conditions of use existed in the OTC • Intramuscular injection for providers determine the proper use of drug marketplace on or before May 11, vaccination preoperative and preinjection antiseptic 1972. Conditions of use include active • Intramuscular injection for delivery of products. ingredient, dosage form and dosage medication, such as an antibiotic or strength, route of administration, and an anesthetic (for trigger point 5. Food Handler Antiseptics the specific OTC use or indication of the injection) product. If the eligibility of a product for • Intradermal injection for tuberculin (Comment 5) Several comments OTC Drug Review is in question, FDA testing requested that FDA formally recognize must have actual product labeling or a • Subcutaneous injection of insulin antiseptic hand washes and rubs used in facsimile of labeling that documents the • Subcutaneous placement of needles the food industry as a distinct food conditions of marketing the product for acupuncture handler category subject to its own • before May 1972 (see § 330.10(a)(2)). If Venipuncture for blood drawing for monograph. The comments also benzethonium chloride was the active laboratory testing requested that FDA confirm that food • ingredient in a drug before May 1972 for Intradermal injection for allergy skin handler antiseptics can continue to be use as a health care personnel hand rub testing marketed until FDA issues a food and/or surgical hand rub, then it would Examples of procedures that are not handler monograph. be eligible for the OTC Drug Review for covered by the preinjection claim (Response 5) As stated in the 2016 those indications. include the following: Consumer Wash Final Rule (81 FR We disagree with the comment’s • Venous catheterization for blood 61106 at 61109) and the 2015 Health statement asserting that donation Care Antiseptic PR (80 FR 25166 at methylbenzethonium chloride (the • Venous catheterization for an 25168), we continue to classify the food active ingredient in Bactine) is extended delivery of medication, such handler antiseptic washes as a separate essentially equivalent to benzethonium as slow infusion of an antibiotic and distinct monograph category. As chloride based on their similar structure • Venous catheterization for delivery of explained in those rulemakings, food and chemical function (both are intravenous fluid handler antiseptic products are not part quaternary ammonium chloride • Placement of a central venous catheter of these rulemakings on the health care antiseptic ingredients). Although these for any purpose and consumer antiseptic monographs. two ingredients are chemically similar • Placement of a heparin lock We continue to believe a separate such that they could be grouped as • Placement of an arterial catheter category is warranted because of quaternary ammonium compounds, • Surgical procedure additional issues raised by the public they are not equivalent molecules. As stated in the 2015 Health Care health consequences of foodborne Furthermore, although not suggested by Antiseptic PR (80 FR 25166 at 25176), illness, differences in frequency and the comment, there is no evidence that the effectiveness criteria for health care type of use, and contamination of the methylbenzethonium is a prodrug for antiseptics are based on the premise that hands by grease and other oils. benzethonium chloride, or requires

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

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surgical hand rubs, and patient parties may have the option to submit no clinical trials presented that showed preoperative skin preparations (80 FR a time and extent application under a definitive clinical benefit for a health 25166 at 25169). As a result of these § 330.14 (21 CFR 330.14) of FDA’s care antiseptic. However, recently, using distinctions, we proposed that alcohol regulations to request that the Agency an active comparator, Tuuli et al. was ineligible for use as a health care amend the health care antiseptic demonstrated fewer infections following personnel hand wash and surgical hand monograph to include these active caesarean section with use of an scrub because the only health care ingredients for use in health care approved patient preoperative health antiseptic products that contained antiseptics for the specified indications. care antiseptic (Ref. 6). Otherwise, we alcohol for which evidence was have seen very few examples of well- submitted to the OTC Drug Review for D. Comments on Effectiveness and FDA controlled studies of this type to date. evaluation were products that were Response Participants at the March 2005 NDAC intended to be used without water (i.e., 1. Clinical Simulation Studies meeting also believed it would be unethical to perform a hospital trial rubs and skin preparations) (Id. at (Comment 10) One comment stated using a vehicle control instead of an 25172). that FDA should require the same We disagree with the comment’s antiseptic given the concerns with clinical studies that were required to assertions that manufacturers did not performing placebo-controlled studies show a benefit of OTC consumer have notice or an opportunity to submit on patients (Ref. 3). The inclusion of antiseptic washes over and above information to the OTC Drug Review on such control arms in a clinical outcome washing with non-antibacterial soap for alcohol’s eligibility for use as a surgical study conducted in a hospital setting OTC antiseptics used in the health care hand scrub. First, we note that the 1994 could pose an unacceptable health risk setting. The comment asserted that there TFM was a proposed rule, not a final to study subjects (hospitalized patients rule; we proposed, but had not yet are numerous safety concerns with the and health care providers). In such found, alcohol to be GRAS/GRAE for use of these active ingredients and given studies, a vehicle or negative control use in surgical hand scrub products. these concerns and health care workers’ would be a product with no Moreover, in the 2015 Health Care extensive exposure to these ingredients antimicrobial activity. The use of Antiseptic PR, our proposal that alcohol in their workplaces on a daily basis, the vehicle or saline (a negative control) in was ineligible for use as a surgical hand Agency should find that there is a a hospital setting (a setting with an scrub also was a preliminary benefit over and above washing with already elevated risk of infections) determination based on the lack of plain soap and water in order to make could increase the risk of infection for adequate evidence of eligibility for a GRAE determination for these active both health care providers and their evaluation under the OTC Drug Review. ingredients. The comment stated that if patients. For these reasons, we continue In the proposed rule, we invited parties FDA relies on bacterial reduction as a to find that the use of clinical to submit such evidence of eligibility. proxy for effectiveness in the health care simulation studies relying on surrogate We explained that if the documentation setting, it must require that that endpoints to evaluate the effectiveness demonstrated that an active ingredient reduction be compared against plain of health care antiseptics is the best met the OTC Drug Review requirements, soap and water, especially given that means available of assessing the the active ingredient could be workers in the health care setting likely effectiveness of health care antiseptic determined to be eligible for evaluation wash their hands more frequently than products. for the specified use. Parties had 180 the general public, and thus, are (Comment 11) Given the ethical days to submit comments on the exposed to higher levels of these concerns with performing clinical trials proposed rule and 12 months to submit ingredients. in a health care setting, one comment any new data or information on the (Response 10) As we explained in the urged FDA to evaluate natural proposed rule, including evidence and 2015 Health Care Antiseptic PR (80 FR experiments that have already occurred documentation on eligibility (80 FR 25166 at 25175 to 25176), study design (e.g., hospital systems that switched 25166 at 25169). The comment limitations and ethical concerns prevent away from chemical antiseptics in hand submitted in response to the 2015 the use of clinical outcome studies to washes) when making a final Health Care Antiseptic PR on this issue demonstrate the effectiveness of active monograph decision. The comment also did not include any documentation or ingredients used in health care stated that, while the clinical simulation evidence to demonstrate that alcohol is antiseptic products. Participants at the studies provide useful information eligible for use as a surgical hand scrub March 2005 NDAC meeting about one possible route through which under the OTC antiseptic monograph, acknowledged the difficulty in bacterial illnesses are passed in a health despite the opportunity to include such designing clinical trials to demonstrate care setting, as currently designed these information. Also, there was no the impact of health care antiseptics on studies do not study the complex additional data or information rates of infection where numerous microflora of the hospital environment, submitted to the record thereafter to factors contribute to hospital-acquired which is home to a wide range of demonstrate alcohol’s eligibility for infections, and therefore, would need to bacterial populations. The comment evaluation under the OTC Drug Review be controlled for in the design of these said that the bactericidal effectiveness of for use as a surgical hand scrub. types of studies. Participants at the the active ingredients is only partially For these reasons, we find that March 2005 NDAC meeting achieved with the in vitro testing. The alcohol continues to be ineligible for recommended that manufacturers comment explained that, in addition to evaluation under the OTC Drug Review perform an array of trials to look the MIC and time-kill testing, the in for use as a surgical hand scrub. simultaneously at the effect on the vitro tests for health care antiseptics Consequently, drug products containing surrogate endpoint and the clinical could mirror the ‘‘worst-case’’ real- alcohol for use in surgical hand scrubs endpoint to try to establish a link world assumptions. Clinical isolates will require approval under an NDA or between the surrogate and clinical that closely represent worst-case ANDA prior to marketing. endpoints, but provided no guidance on hospital or health care microbial We also note that where these active possible study designs. At the time, populations (e.g., large numbers of ingredients are ineligible for evaluation participants at the March 2005 NDAC multi-drug resistant bacterial strains) under the OTC Drug Review, interested meeting agreed that there were currently could be highly useful in determining

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the effectiveness of an active ingredient reductions that would be achieved to make the 70 percent success rate for under real-world conditions. The under such conditions of use. abdomen, no products can make the 70 comment stated that worst-case percent success rate for the groin area at 2. Log Reduction Testing Criteria assumptions could include patient- 30 seconds. One comment agreed with derived isolates from cases involving (Comment 12) Multiple comments the 30-second time point, but argued isolation due to multi-drug resistance or were submitted to the 2015 Health Care that sampling should include a time isolates from frequently contaminated Antiseptic docket on the in vivo testing point after the drying time is completed surfaces within a hospital or health care criteria that use bacterial log reductions according to the directions. The setting (e.g., door knobs, soap for determining the effectiveness of comment stated that, in the proposed dispensers); and that this type of testing active ingredients used in health care amendment to the 1994 TFM, it is could be expanded into ‘‘clinical antiseptic products. One comment unclear whether the antiseptic would be simulation’’ studies by measuring log stated that single application testing and tested 30 seconds after application and reduction of bacterial counts on hands increased log reduction for health care while still wet, potentially resulting in contaminated under actual health care personnel hand rubs is not supported by efficacy compromise. The comment conditions. scientific evidence and that current gaps asserted that FDA should allow the (Response 11) We believe that exist within the peer-reviewed product to fully dry before collecting 30- applying health care-associated high literature. The comment recommended second time point efficacy testing, risk microbial pathogens (e.g., that the Agency not change the testing especially with topical skin antiseptics, methicillin-resistant Staphylococcus requirements for the health care because it is important that the skin be aureus) during clinical simulation personnel hand rub products because fully dry to achieve maximum efficacy studies raises the ethical and study alcohol-based hand rubs are used and also to minimize potential skin millions of times a day across the design issues we have discussed in this irritation associated with use. Similarly, United States in all health care facilities. rulemaking. Currently, no historical another comment asserted that, when The comment also asserted that the data have been submitted to the docket referring to time points after product recommended changes to the testing that address or evaluate the application for patient preoperative skin requirements by FDA could result in the effectiveness of health care antiseptic preparation, it should be explicitly unavailability of hand hygiene products active ingredients in health care stated that ‘‘after product application’’ to the clinicians who utilize them daily settings. Also, we are not aware of any means ‘‘product application plus to prevent the transmission of health health care personnel hand wash required dry time.’’ Several comments care associated infections to patients. antiseptic that has been replaced with also stated that the proposed 10-minute One comment also asserted that FDA the use of plain soap and water in the application period identified in the should retain the effectiveness criteria 1994 TFM is more representative of hospital setting, and no such data have proposed for surgical hand scrubs been submitted to the docket. Moreover, current clinical application practices. identified in the 1994 TFM for single (Response 12) As described in the as explained in this rulemaking, applications only. 2015 Health Care Antiseptic PR, we participants at the March 2005 NDAC Several comments also asserted that proposed revisions to the log reduction meeting believed that it would be FDA should retain the effectiveness criteria for health care personnel hand unethical to perform hospital trial criteria proposed in the 1994 TFM for washes and rubs, and for surgical hand studies using a vehicle control, such as health care personnel hand wash and scrubs and rubs based on the plain soap and water, instead of an rub products as 2 log10 after a single recommendations of the March 2005 antiseptic. application. The comments argued that NDAC meeting and comments to the In addition, the standard infection the proposed 2.5 log10 reduction with a 1994 TFM that argued that the control guidance broadly implemented 70 percent success criterion for health demonstration of a cumulative by CDC (Refs. 7 and 8), which involves care personnel hand wash products antiseptic effect for these products is measures such as gloving, hand hygiene, would be unattainable even by current unnecessary (80 FR 25166 at 25178). We patient-to-patient contact, and waste FDA-approved products. In addition, agreed that the critical element of disposal, makes it difficult to design an several comments suggested that FDA effectiveness is that a product must be adequate clinical study (Ref. 9). adopt effectiveness criteria for in vivo effective after the first application Moreover, the in vitro testing required effectiveness testing of active because that represents the way in for proof of effectiveness against ingredients in surgical hand rubs and which health care personnel hand microorganisms (80 FR 25166 at 25177 scrubs of a 1 log10 reduction within one washes and rubs and surgical hand to 25178), is already intended to minute after the first application scrubs and rubs are used. Given that we characterize the activity (broad procedure with no return to baseline were no longer requiring a cumulative spectrum) of the antimicrobial within 6 hours. antiseptic effect, the log reduction ingredient. The American Type Culture Several comments also asserted that it criteria were revised to reflect this Collection (ATCC) strains we reference is inappropriate to propose a 30-second single product application and fall in the 2015 Health Care Antiseptic PR contact time for patient preoperative between the log reductions previously for the in vitro testing are chosen to skin preparations. The comments proposed for the first and last represent a broad spectrum of bacteria argued that most active ingredients for application. Accordingly, we continue that present a challenge to antisepsis use in patient preoperative skin to find that the log reduction criteria for and are the principal bacterial preparations would be unable to make these products should be applied to a pathogens encountered in hospital the log reduction effectiveness criteria at single application of the product rather settings. The clinical simulation studies 30 seconds. The comments asserted than to multiple applications of the described in the 2015 Health Care that, although it may be possible for product. Antiseptic PR are based on the premise some patient preoperative skin Moreover, in the 2015 Health Care that bacterial reductions achieved using preparation products to make the log Antiseptic PR, we also proposed that tests that simulate conditions of actual reduction effectiveness criterion and patient antiseptic skin preparations (i.e., use for each OTC health care antiseptic that it may be possible for some patient patient preoperative and preinjection product category reflect the bacterial preoperative skin preparation products skin preparations) be able to

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demonstrate effectiveness at 30 seconds superiority to negative control and a 95 vehicle or saline, may exhibit some because we believed that injections and percent confidence interval approach minimal antimicrobial properties. Thus, some incisions are made as soon as 30 (80 FR 25166 at 25178 to 25179). FDA using superiority to negative control by seconds after skin preparation (80 FR also recommended that the success rate those margins will help ensure that we 25166 at 25178). In vivo studies are or responder rate of the test product be can appropriately assess the based on the premise that bacterial significantly higher than 70 percent. effectiveness of the deferred reductions achieved using tests that This meant that the lower bound of the antimicrobial products. The margins we simulate conditions of actual use for 95 percent confidence interval for the identify in this section were derived each health care antiseptic category proportion of subjects who met the log from review and analysis of existing reflect the bacterial reductions that reduction criteria was expected to be at data, and may be revised as data gaps on would be achieved under conditions of least 70 percent. deferred antimicrobial products are such use. Accordingly, we find that the Consistent with the 1994 TFM and filled. Because of existing data gaps, we effectiveness criteria for patient 2015 Health Care Antiseptic PR, we find also require the deferred ingredient to antiseptic skin preparations (i.e., patient that bacterial log reduction studies show non-inferiority to active controls preoperative and preinjection skin should continue to be used to by a 0.5 margin (log10 scale). preparations) should continue to demonstrate that an active ingredient is Accordingly, based on the updated include the 30-second sampling time effective for use in a health care analysis, the bacterial log reduction point. Also, we find that the 10-minute antiseptic product. Also consistent with studies used to assess whether an active sampling time point proposed in the the 2015 Health Care Antiseptic PR, ingredient is effective for use in health 1994 TFM should also be included in subjects should be randomized to a care antiseptics should include the the effectiveness criteria as a time point three-arm study: Test, active control, following: option for patient preoperative skin and negative control. However, based on • The test product should be non- preparations. These products should be comments submitted on the 2015 Health inferior to an FDA-approved active tested at the 30-second or 10-minute Care Antiseptic PR and the Agency’s control with a 0.5 margin (log10 scale). sampling time point after drying, further evaluation of additional data, we That is, we expect the upper bound of according to the labeled directions for are updating the statistical analysis the 95 percent confidence interval of the use. For patient preinjection skin related to the log reduction criteria for ATE of the active control compared to classifying health care antiseptic active preparations, however, the 10-minute the test product to be less than 0.5 (log10 sampling time point should not be a ingredients as GRAE. Also, as we scale). An active control is not intended time point option. Patient preinjection explain in section V.B.4, we include to validate the study conduct or to show skin preparations should be tested at the separate effectiveness criteria for patient superiority of the test drug product but 30-second time point only. preinjection skin preparations to more to show that the test drug product is not Based on comments submitted on the accurately reflect the actual use of these inferior. Non-inferiority to active control 2015 Health Care Antiseptic PR and the products. We also clarify, for patient should be met at the following area and Agency’s further evaluation of preoperative skin preparations and times for the respective health care additional data, we have updated the patient preinjection skin preparations, antiseptic indications: underlying statistical analysis related to that the sampling time point Æ Patient preoperative skin the log reduction criteria for classifying commences after the applied product preparation: health care antiseptic active ingredients dries. D as GRAE (Refs. 10, 11, 12, 13, 14, and The updated analysis is designed to Per square centimeter on abdominal 15). assess whether the average treatment site within 30 seconds after drying, In the 1994 TFM, FDA recommended effects (ATE) across subjects meet or within 10 minutes after drying that the general effectiveness of indication-specific conditions of D Per square centimeter on groin site antiseptics be assessed in a number of superiority and non-inferiority, rather within 30 seconds after drying, or within 10 minutes after drying ways, including conducting clinical than whether the percentage of subjects Æ simulation studies with the surrogate who meet an indication-specific Patient preinjection skin preparation: endpoint of the number of bacteria threshold significantly exceeds 70 Per square centimeter on a dry site removed from the skin. In the 2015 percent. More specifically, the updated (i.e., forearm, abdomen, or back) Health Care Antiseptic PR, FDA made analysis estimates the ATE from a linear within 30 seconds after drying Æ revisions to the effectiveness criteria set regression of post-treatment bacterial Health care personnel hand wash: On each hand within 5 minutes after a forth in the 1994 TFM, while continuing count (log10 scale) on the additive effect to recommend that bacterial log of a treatment indicator and the baseline single wash Æ Health care personnel hand rub: On reduction studies be used to or pre-treatment measurement (log10 demonstrate that an active ingredient is scale). In the conditions below, the ATE each hand within 5 minutes after a GRAE for use in a health care antiseptic of the test product compared to the single rub. Æ product. FDA recommended that these negative control is defined as the Surgical hand scrub: On each hand bacterial log reduction studies: (1) contrast of treatment effect of negative within 5 minutes after a single Include both a negative control (test control minus the treatment effect of the scrub Æ product vehicle or saline solution) and test drug in the linear regression. Surgical hand rub: On each hand an active control; (2) have an adequate Likewise, the ATE of the active control within 5 minutes after a single rub sample size to show that the test compared to the test product is defined • The test product should be superior product is superior to its negative as the contrast of treatment effect of test to the vehicle control by an indication- control; (3) incorporate the use of an product minus the treatment effect of specific margin. That is, we expect the appropriate neutralizer and a the active control in the linear lower bound of the 95 percent demonstration of neutralizer validation; regression. confidence interval of the ATE of the and (4) include an analysis of the Superiority to negative control by a test product compared to the vehicle proportion of subjects who meet the specific margin is needed because our control to be greater than the indication- recommended log reduction criteria evaluation suggests that application of a specific margin. In cases where the based on a two-sided statistical test for negative control, whether test product’s vehicle cannot be used as a negative

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control, nonantimicrobial soap or saline 3. Baseline Bacterial Count negative control. The number of viable solution can be used. Based on our (Comment 13) Several comments microorganisms recovered from the skin evaluation of the existing data, the asserted that the Agency does not of each subject at baseline should be following indication-specific superiority specify a minimum baseline bacterial provided in the final study report. In margin should be met by the deferred count for subject eligibility in the addition, given the updated statistical analysis criteria outlined in section ingredients for the respective health clinical simulation studies and that the V.D.2, it is unnecessary to apply the care antiseptic indications: 1994 TFM is vague with regard to Æ baseline values for patient preoperative Superiority margin of 1.2 log10 for baseline values. The 1994 TFM states skin preparations that follow the ASTM patient preoperative skin only that sites are to possess bacterial E1173 method. preparation populations large enough to allow D per square centimeter on abdominal Moreover, if manufacturers find it demonstrations of bacterial reduction of challenging to recruit subjects who have site within 30 seconds after drying, up to 2 log10 per square centimeter on or within 10 minutes after drying resident bacterial counts high enough to dry skin sites and 3 log10 per square be eligible for these studies, we D per square centimeter on groin site centimeter on moist sites (59 FR 31402 within 30 seconds after drying, or recommend the use of the back as an at 31450). One comment urged FDA to alternate dry test site, rather than using within 10 minutes after drying use baseline values for patient Æ the arm. We do not recommend the use Superiority margin of 1.2 log10 for preoperative skin preparations that patient preinjection skin of an occlusive dressing (sterile gauze). follow the American Society for Testing Covering the test sites has the potential preparation per square centimeter and Materials (ASTM) 3 method E1173, on a dry site (i.e., forearm, to change the make-up of the microbial which is more specific and states that population. Therefore, the use of abdomen, or back) within 30 the bacterial baseline population should seconds after drying occlusion may not provide an accurate be at least 3 log10 per square centimeter assessment of how effective the product Æ Superiority margin of 1.2 log10 for on moist skin sites and at least 2 log10 will be under actual use conditions. health care personnel hand wash on greater than the detection limit on dry each hand within 5 minutes after a skin sites. Several comments also stated 4. Persistence single wash that it was challenging to find subjects Æ (Comment 14) One comment stated Superiority margin of 1.5 log10 for who have resident bacterial counts high that current infection control health care personnel hand rub on enough to be eligible for these studies. procedures make persistence of each hand within 5 minutes after a (Response 13) We do not specify a antimicrobial activity for surgical hand single rub Æ minimum baseline bacterial count for scrub and patient preoperative skin Superiority margin of 0.5 log10 for subject eligibility in the clinical preparations irrelevant. The comment surgical hand scrub on each hand simulation studies; however, the test asserted that persistence of effect may, within 5 minutes after a single sites should possess bacterial in fact, be a negative attribute for these scrub Æ populations large enough to meet the products because it may cause irritation. Superiority margin of 1.5 log10 for updated statistical criteria as explained The comment suggested that the Agency surgical hand rub on each hand in section III.D.2. We do not specify a place more emphasis on the mildness of within 5 minutes after a single rub minimum baseline bacterial count these products rather than the As discussed in more detail in section because, as explained in section III.D.2, persistence of these products. Another V.D.4, we believe that persistence of the ATE is used to demonstrate comment agreed with the Agency’s antimicrobial effect is an important effectiveness. Rather than using only a requirement that patient preoperative attribute for health care antiseptic change from baseline, each criterion skin preparations and surgical scrubs products, and in particular for patient (groin site and abdomen site) uses the have a persistent antimicrobial effect. preoperative skin preparations, surgical ATE, an estimated difference of the Another comment contended that the hand scrubs, and surgical hand rubs. To effect of two treatments correcting for Agency’s statement about the need for show persistence of effect for these baseline count. Manufacturers are persistence of effect for patient health care antiseptic indications, the 6 encouraged to select subjects with preoperative hand scrubs lacks hours post-treatment measurement baseline counts significantly higher than substantiating data. Another comment should be lower than or equal to the the expected log reductions achieved stated that the concept of persistence of baseline measurement for 100 percent of during the testing (i.e., high enough to antimicrobial activity is not consistent the subjects in each indication and body allow for a positive residual of bacterial for surgical scrub and patient area tested. burden after the use of the active control preoperative skin preparations, nor is it Moreover, for the deferred and the test product). This selection will consistent with clinical practice. The ingredients, a minimum sample size of ensure that there is a high enough comment asserted that the testing 100 subjects per treatment arm should bacterial count at baseline to assess the requirements for a patient preoperative be included for each indication. This full effectiveness of both the active skin preparation limit the definition of sample size will ensure that ATE will be control and the product under persistence to 6 hours of sustained estimated precisely for the deferred evaluation. Likewise, a bacterial burden activity after each product use. The ingredients and can be used for future so low that it is depleted readily both by comment recommended that persistence reference in final product monographs. the vehicle (or negative control) and by for surgical hand scrub products be Exact sample size can be based on the the test product, will not allow for an defined as sustained activity of the margins for non-inferiority and assessment of the effectiveness of that antimicrobial formulation for a period of superiority as well as an assessment of test product because the outcome would 6 hours after product use. Another variability. In addition, two adequate equally be zero and it will not be comment asserted that persistence and well-controlled clinical simulation possible to measure the difference in log should not be required for any of the pivotal studies should be conducted for reduction between the test product and health care indications. each indication at two separate (Response 14) In the 1994 TFM, we independent laboratory facilities by 3 General information about ASTM International described the importance of persistence independent principal investigators. can be found at https://www.astm.org/. as a characteristic of antiseptic drug

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

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drug product, but to show that the test and kinetics of antimicrobial activity of (Response 17) We agree that the drug product is not inferior. a health care antiseptic as including the determination of the in vitro spectrum In addition, we recommend the use of following: of antimicrobial activity against recently an active control product of the same • A determination of the in vitro isolated normal flora and cutaneous type as the test product. For example, if spectrum of antimicrobial activity pathogens is meant to describe what the test product is a leave-on surgical against recently isolated normal flora will be learned from the MIC and/or hand antiseptic, then an FDA-approved and cutaneous pathogens; MBC and time-kill studies and is not leave-on surgical hand antiseptic should • Minimum inhibitory concentration intended to be a separate study. With be used as the active control rather than (MIC) or minimum bactericidal regards to testing for the emergence of a rinse-off surgical hand antiseptic. We concentration (MBC) testing of 25 resistance, we are requiring resistance believe it is more appropriate to representative clinical isolates and 25 testing for three of the six deferred compare similar types of products. reference strains of each of the active ingredients—benzalkonium (Comment 16) One comment stated microorganisms listed in the 1994 TFM; chloride, benzethonium chloride, and that a vehicle typically refers to the and chloroxylenol (Refs. 10, 11, 12, 13, 14, product formulated without the active • Time-kill testing of each of the and 15). However, we are not requiring ingredient. The comment recommended microorganisms listed in the 1994 TFM resistance testing for the other three that the term ‘‘vehicle’’ be replaced with to assess how rapidly the antiseptic deferred active ingredients—ethyl the term ‘‘negative control.’’ Another active ingredient produces its effect. alcohol, isopropyl alcohol, and comment requested that FDA clarify The dilutions and time points tested povidone-iodine (see section V.D.2). whether testing of the vehicle is should be relevant to the actual use In addition, we disagree that we are required. pattern of the final product. suggesting that previous tests of the (Response 16) We recognize that the The comment requested that we confirm same or similar strains are no longer term ‘‘negative control’’ may be broader that the first bullet is meant to describe valid. In the 2015 Health Care than the term ‘‘vehicle,’’ and we agree what will be learned from the studies Antiseptic PR, we proposed the option that the term ‘‘vehicle’’ should be outlined in the last two bullets because of assessing the MBC as an alternative replaced with the term ‘‘negative they do not recognize the first bullet as to testing the MIC. We also reiterated control’’ where applicable. As discussed an actual study. The comment also our proposal that the evaluation of the in section V.D.2, we recommend that asked for confirmation that the spectrum and kinetics of antimicrobial the effectiveness testing study design for emergence of resistance testing is no activity of health care antiseptic active health care antiseptic active ingredients longer a requirement. ingredients should include MIC (or include a negative control arm, which is Another comment stated that the MBC) testing of 25 representative used as a comparator for the test Agency has proposed in vitro testing of clinical isolates and 25 reference (e.g., product. The appropriate negative 1,150 microorganisms (25 clinical ATCC) strains of each of the control to be used in the studies is the isolates and 25 reference isolates for 23 microorganisms listed in the 1994 TFM, test product’s vehicle, which we microorganisms). The comment argued in addition to the other proposed interpret to be the same product being that the Agency’s suggestion that requirements. In the 2015 Health Care tested, without the active ingredient previous tests of the same or similar Antiseptic PR, we noted that, despite included, and therefore, best represents strains are no longer valid is arbitrary the fact that the in vitro data submitted the independent contribution of the and that the requirement for new to support the effectiveness of antiseptic antiseptic active ingredient. Because the repeated tests is unduly burdensome. active ingredients were far less same directions for use will apply to the The comment asserted that the proposed extensive than proposed in the 1994 negative control and the test product, number of clinical and reference isolates TFM, manufacturers may have data this should account for any potential far exceeds the number required for from their own product development mechanical removal of microorganisms, FDA-approved hand hygiene products, programs which they have not which occurs during the rubbing, which have successfully completed the submitted to the docket and/or that scrubbing, wiping, or rinsing process, review process. The comment published data may have become independent of the active ingredient recommended that organisms of current available that would satisfy some or all effect. If there is a scientific reason why clinical value as well as recent clinical of the data requirements (80 FR 25166 testing a product using its vehicle as a isolates be utilized to better assess the at 25178). negative control is not feasible, in vitro efficacy of these active As we explained in the 2015 Health discussions can be had with FDA to ingredients. Another comment similarly Care Antiseptic PR, we agree that the in determine whether the use of an asserted that the microorganisms vitro testing proposed in the 1994 TFM alternative negative control, such as a identified by FDA for antimicrobial is not necessary for testing every final saline solution or nonantimicrobial soap activity testing do not include formulation of an antiseptic product (for health care personnel and surgical pathogens that are relevant to current that contains a GRAE ingredient (80 FR hand antiseptics), may be acceptable. health care settings; the comment 25166 at 25177). However, we continue We note that the testing described in argued that the list should include to believe that a GRAE determination for this document pertains to single active Methicillin-resistant Staphylococcus health care antiseptic active ingredients ingredients. Manufacturers should aureus, Methicillin-resistant should be supported by adequate in contact us if, in the future, they would Staphylococcus epidermidis, vitro characterization of the like to develop a fixed-combination Vancomycin-resistant Enterococcus; antimicrobial activity of the ingredient. health care antiseptic drug product. Enterococcus faecalis and Enterococcus We note that, for the six deferred active faecium). Another comment proposed ingredients, the Agency is reviewing 6. In Vitro Testing that FDA should consider adequate proposed protocols for the safety and (Comment 17) One comment outlined justifications for testing fewer than the effectiveness studies, including the list the Agency’s proposed requirements identified strains for organisms where of organisms for the time-kill testing and listed in the 2015 Health Care 25 clinical isolates and/or 25 standard MIC/MBC testing, which may include Antiseptic PR (80 FR 25166 at 25177 to strains are not available for screening additional resistant organisms that are 25178) for an evaluation of the spectrum active ingredients. relevant to current health care settings.

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7. American Society for Testing and antiseptic active ingredients. The standards are reasonable and considered Materials Standards comment agreed that more testing is them to be minimal safety standards for (Comment 18) Several comments needed to support a GRAS currently available, as well as future proposed that the Agency recognize determination for these active healthcare antiseptic products (Ref. 19). specific ASTM protocols as ingredients. Other comments, however, Moreover, the long history of use of a standardized test methods for asserted that the safety testing proposed drug product is not sufficient to demonstrating that an active ingredient in the 2015 Health Care Antiseptic PR demonstrate the safety of the product. In is GRAE for use in health care for active ingredients used in health the case of antiseptic products, the antiseptics and demonstrating care antiseptics is unnecessary and Agency has requested safety data in effectiveness for final product burdensome. The comments asserted both the 1994 TFM and the 2015 Health formulations. These ASTM test methods that FDA has not provided data to Care Antiseptic PR in order to finalize include the ASTM E1174 ‘‘Standard justify that additional safety data are the antiseptic rules. Relying solely on Test Method for the Evaluation of the needed for these ingredients to make a adverse event reporting cannot fill data Effectiveness of Health Care Personnel GRAS determination and stated that the gaps regarding risks such as Handwash Formulations’’; the ASTM extensive historical use of these reproductive toxicity or carcinogenicity. E2755–10 ‘‘Standard Test Method for products should serve as proof of the As an example, phenolphthalein was an Determining the Bacteria-Eliminating products’ safety and effectiveness. OTC product with a long history of use Effectiveness of Hand Sanitizer Another comment stated that FDA as a laxative, but when animal studies Formulations Using Hands of Adults’’; must document how the systemic were conducted, evidence of the ASTM E1115–11 ‘‘Standard Test absorption levels of active ingredients carcinogenicity was detected. The April Method for Evaluation of Surgical Hand from the use of health care antiseptics 30, 1997, FDA Center for Drug Scrub Formulations’’; the ASTM E1173– differ from FDA’s previous assessment Evaluation and Research (CDER) 15 ‘‘Standard Test Method for of the safety of these ingredients. The Carcinogenicity Assessment Committee Evaluation of Preoperative, comment asserted that, given the lack of (CAC) meeting concluded that there was Precatheterization, or Preinjection Skin information on FDA’s current position supportive evidence indicating that Preparations’’; the ASTM E1054 on the specific details regarding risk phenolphthalein may be carcinogenic ‘‘Standard Test Methods for Evaluation assessment, FDA should consider in through a genotoxic mechanism. FDA of Inactivators of Antimicrobial vitro data and dose-extrapolation data. concluded ‘‘phenolphthalein caused Another comment suggested that Agents’’; the ASTM E2783 ‘‘Standard chromosome aberrations, cell long-term systemic exposure to active Test Method for Assessment of transformation, and mutagenicity in ingredients used in health care mammalian cells. Because benign and Antimicrobial Activity for Water antiseptics could be reduced if the malignant tumor formation occurs at Miscible Compounds Using a Time-Kill efficacy standards for these products multiple tissue sites in multiple species Procedure’’; and the Clinical and were decreased because lower dose of experimental animals, Laboratory Standards Institute M07– products could be formulated. phenolphthalein is reasonably A10 ‘‘Methods for Dilution (Response 19) We continue to believe anticipated to have human carcinogenic Antimicrobial Susceptibility Tests for that the additional safety data outlined potential.’’ This conclusion led to the Bacteria That Grow Aerobically.’’ in the 2015 Health Care Antiseptic PR (Response 18) For purposes of the six removal of phenolphthalein from the are necessary to support a GRAS market (64 FR 4535, 4538) (Ref. 20). deferred active ingredients, we have classification for the health care Finally, in this context, the safety data reviewed these test methods and believe antiseptic active ingredients. As was required to make a final GRAS they may be useful to help establish explained in the 2015 Health Care determination on active ingredients GRAE status for the health care Antiseptic PR, several important used in health care antiseptic products antiseptic products for their respective scientific developments that affect the would remain the same even if FDA indications. We are currently discussing safety evaluation of the health care determined that the data requirements with manufacturers and trade antiseptic active ingredients have necessary to make a GRAE organizations that requested the occurred since FDA’s 1994 evaluation. determination should be changed. deferrals how these test methods may be New data and information on the health (Comment 20) Several comments also used to meet the current effectiveness care antiseptic active ingredients raise stated that the additional testing criteria. concerns regarding potential risks from requirements could cause disruptions of Testing requirements for final systemic absorption and long-term the availability of health care antiseptics formulation, however, are not addressed exposure, as well as development of for clinical use. One comment urged the in this final rule because none of the bacterial resistance related to Agency to fully consider the active ingredients subject to this final widespread antiseptic use (80 FR 25166 consequences of the additional testing rule have been found to be GRAE for use at 25167). Data that meet current safety requirements, especially at a time when in health care antiseptic products. The standards are needed for FDA to hand hygiene is considered to be the testing requirements for final conduct an adequate safety evaluation cornerstone for preventing the spread of formulation of these products to ensure that health care antiseptic pathogenic organisms in health care containing the six deferred active active ingredients are GRAS. Moreover, settings. ingredients will be addressed after a as previously explained in this (Response 20) We agree that health decision is made regarding the document, the September 2014 NDAC care antiseptic products are an monograph status of those ingredients. meeting participants discussed FDA’s important component of infection E. Comments on Safety and FDA proposed revisions to the safety data control strategies in health care settings Response requirements and agreed that these and remain the standard of care to requirements were appropriate to prevent illness and the spread of 1. Need for Additional Safety Data demonstrate that a health care antiseptic infections (Refs. 7 and 8). As we (Comment 19) One comment active ingredient is GRAS. Participants emphasized in the 2015 Health Care supported FDA’s proposal to require at the September 2014 NDAC meeting Antiseptic PR, our proposal for more additional safety data for the health care further concluded that these safety safety and effectiveness data for health

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

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

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

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

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

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drug, FDA uses data in which a control (Response 33) We agree that the investigators. FDA is willing to review group is included in the study to impact of exposure to sensitive all relevant available data in order to compare to the treatment groups. A populations should be considered. Our reach a final determination of safety and prospective NHS study evaluating the paradigm of safety evaluation, which effectiveness. Ultimately, manufacturers effect of exposure to the active includes a battery of safety studies are responsible for the safety and ingredients in health care antiseptics (ADME, MUsT, carcinogenicity, DART, effectiveness of the drug products they would require a control group in which and hormonal effects), can be used to market. there is no exposure to health care establish a safety margin for potential (Comment 36) One comment antiseptic active ingredients. However, safety signals in all populations, contended that NDA products, such as because all nurses in health care including sensitive ones. Avagard (1 percent chlorhexidine environments in which NHS studies Currently, the effect of health care gluconate, 62 percent ethyl alcohol) have been conducted have to adhere to antiseptic active ingredients on the should be subject to the safety standards a universal hand washing protocol using microbiome have not been included as proposed in the 2015 Health Care antiseptic active ingredients, it is not a safety signal in classifying an active Antiseptic PR. possible to include a control group with ingredient as GRAS or non-GRAS. FDA (Response 36) FDA regulates NDA no exposure to healthcare antiseptics in will continue to monitor emerging products under a different regulatory a NHS study. technologies that can help address pathway than the OTC drug monograph We also note that the safety signals safety signals for all of the products that products, such as the OTC health care FDA uses in making a GRAS it regulates, including products under antiseptics that are the subject of this determination, such as developmental the OTC topical antiseptic monograph. rulemaking. We consider safety criteria and reproductive toxicity, In addition, because there are many for both monograph and NDA products. carcinogenicity, or hormonal effects, disease states which health care The review of an individual product would not likely be reported by professionals or patients could have, it under an NDA may warrant a different consumers or health care professionals is not feasible to develop metabolic assessment than a group of active to MedWatch. Thus, the lack of parameters for individual disease states ingredients used in a range of products. in conducting the GRAS determinations MedWatch safety-related reports does F. Comments on the Preliminary of the active ingredients used in health not eliminate the need for the safety Regulatory Impact Analysis and FDA care antiseptic products. Nor could one data outlined in the 2015 Health Care Response prospectively identify which specific Antiseptic PR. metabolic parameters should be tracked, (Comment 37) Several comments (Comment 33) One comment stated or if there were defined levels of raised issues concerning the preliminary that, for FDA to fully assess the safety changes in each parameter that would regulatory impact analysis and the of the health care topical antiseptic be of concern. Agency’s assessment of the net benefit active ingredients, it must consider the (Comment 34) Another comment of the rulemaking. impact of exposure on groups that may stated that FDA needs to address the (Response 37) Our response is be particularly sensitive to exposure, impact of inactive ingredients and final provided in the full discussion of including pregnant women, children, formulations on the safety assessments economic impacts, available in the and the elderly, particularly with of health care antiseptic products. docket for this rulemaking (Docket No. regards to chronic or highly sensitive (Response 34) Testing requirements FDA–2015–N–0101, (Ref. 78), https:// (e.g., newborn infant) exposure. for the final product formulations, www.regulations.gov) and at https:// The comment also proposed that in which would require exposure to both www.fda.gov/AboutFDA/ classifying an ingredient as GRAS/ active and inactive ingredients, are not ReportsManualsForms/Reports/ GRAE, FDA should expand the health addressed in this final rule because EconomicAnalyses/default.htm. impacts (e.g., impact on the none of the active ingredients that are VI. Ingredients Not Generally microbiome) and should consider the subject of this final rule are Recognized as Safe and Effective ‘‘clinically-relevant’’ effectiveness (e.g., considered GRAS/GRAE for use in reduction of bacteria typically found in health care antiseptic products, given No additional safety or effectiveness health care settings). The comment the lack of sufficient effectiveness and data have been submitted to support a added that the final rule should safety data submitted for these GRAS/GRAE determination for the non- incorporate safety standards to protect ingredients. The testing requirements deferred health care antiseptic active populations, outside of health care for final formulations of products ingredients described in this rule. Thus, personnel, that could experience containing the six deferred active the following active ingredients are not increased adverse events upon exposure ingredients will be addressed, if GRAS/GRAE for use as a health care to antiseptic products. The comment applicable, after a decision is made antiseptic: • contended that the effect of antiseptic regarding the monograph status of those Chlorhexidine gluconate active ingredients on the microbiome • Cloflucarban ingredients. • should be more thoroughly considered (Comment 35) One comment Fluorosalan • Hexachlorophene in the final monograph to incorporate indicated that the cost of conducting • the effects into the benefit-to-risk Hexylresorcinol safety studies is expensive and asserted • Iodophors (Iodine-containing calculation. that the testing requirements run ingredients) The comment also asserted that data counter to the spirit of the OTC Æ Iodine complex (ammonium ether used in the safety evaluation of these monograph. The comment proposed sulfate and polyoxyethylene sorbitan ingredients should include metabolic that the safety studies, should therefore, monolaurate) parameters of disease states of be conducted by academic and National Æ Iodine complex (phosphate ester of individuals who would be chronically Institutes of Health (NIH) investigators. alkylaryloxy polyethylene glycol) exposed to health care antiseptics in (Response 35) The monograph process Æ Iodine tincture USP animal pharmacokinetic absorption, is public in nature and studies may be Æ Iodine topical solution USP distribution, metabolism, and excretion conducted by any interested parties, Æ Nonylphenoxypoly (ethyleneoxy) (ADME) models. including academics and NIH ethanoliodine

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Æ Poloxamer—iodine complex and other advantages; distributive 3). To our knowledge, there is only one Æ Undecoylium chloride iodine impacts; and equity). Executive Order ineligible product currently on the complex 13771 requires that the costs associated market, an alcohol-containing surgical • Mercufenol chloride with significant new regulations ‘‘shall, hand scrub, which is affected by this • Methylbenzethonium chloride to the extent permitted by law, be offset rule. • Phenol by the elimination of existing costs Benefits are quantified as the volume • Secondary amyltricresols associated with at least two prior reduction in exposure to triclosan found • Sodium oxychlorosene • regulations.’’ We believe that this final in health care antiseptic products Tribromsalan rule is a significant regulatory action as • Triclocarban affected by the rule, but these benefits defined by Executive Order 12866. This • Triclosan are not monetized. Annual benefits are • Triple dye final rule is considered an Executive estimated to be a reduction in exposure • Combination of calomel, Order 13771 regulatory action. of 88,000 kg of triclosan per year. oxyquinoline benzoate, The Regulatory Flexibility Act Costs are calculated as the one-time triethanolamine, and phenol requires us to analyze regulatory options costs associated with reformulating derivative that would minimize any significant health care antiseptic products • Combination of mercufenol chloride impact of a rule on small entities. containing the active ingredient and secondary amyltricresols in 50 Because we estimate that only four triclosan and relabeling reformulated percent alcohol small businesses will be adversely products, plus the lost producer surplus Accordingly, OTC health care affected by the final rule, we certify that (measured as lost revenues) due to antiseptic drug products containing the final rule will not have a significant removing one alcohol surgical hand these active ingredients will require economic impact on a substantial scrub from the market. We believe that approval under an NDA or ANDA prior number of small entities. the alcohol-containing surgical hand to marketing. The Unfunded Mandates Reform Act scrub that is affected by this rule is of 1995 (Section 202(a)) requires us to likely to be removed from the market. VII. Compliance Date prepare a written statement, which We categorize the associated loss of In the 2015 Health Care Antiseptic includes an assessment of anticipated sales revenue as a transfer from one PR, we recognized, based on the scope costs and benefits, before proposing manufacturer to another and not a cost, of products subject to this final rule, ‘‘any rule that includes any Federal because we assume that the supply of that manufacturers would need time to mandate that may result in the other, highly substitutable, products is comply with this final rule. Thus, as expenditure by State, local, and tribal highly elastic. governments, in the aggregate, or by the proposed in the 2015 Health Care Annualizing the one-time costs over a private sector, of $100,000,000 or more Antiseptic PR (80 FR 25166 at 25195), 10-year period, we estimate total (adjusted annually for inflation) in any this final rule will be effective 1 year annualized costs to range from $1.1 to one year.’’ The current threshold after after the date of the final rule’s $4.1 million at a 3 percent discount rate, adjustment for inflation is $148 million, publication in the Federal Register. On and from $1.2 to $4.7 million at a 7 using the most current (2016) Implicit or after that date, any OTC health care percent discount rate. The present value Price Deflator for the Gross Domestic antiseptic drug products containing an of total costs ranges from $9.0 to $34.6 Product. This final rule would not result ingredient that we have found in this million at a 3 percent discount rate, and in an expenditure in any year that meets final rule to be not GRAS/GRAE cannot from $8.7 to $29.6 million at a 7 percent or exceeds this amount be introduced or delivered for discount rate. introduction into interstate commerce B. Summary of Costs and Benefits In this final rule, small entities will unless it is the subject of an approved bear costs to the extent that they must NDA or ANDA. As discussed in the preamble of this final rule, this rule establishes that 24 reformulate and re-label any health care VIII. Summary of Regulatory Impact eligible active ingredients are not antiseptic containing triclosan that they Analysis generally recognized as safe and produce. The average cost to small firms The summary analysis of benefits and effective for use in OTC health care of implementing the requirements of costs included in this final rule is drawn antiseptics. However, data from the FDA this final rule is estimated to be from the detailed Regulatory Impact drug product registration database $213,176 per firm. The costs of the Analysis that is available at https:// suggest that only one of these 24 changes, along with the small number of www.regulations.gov, Docket No. FDA– ingredients is found in OTC health care firms affected, implies that this burden 2015–N–0101, (Ref. 78). antiseptic products currently marketed would not be significant, so we certify pursuant to the TFM: Triclosan. that this final rule will not have a A. Introduction Regulatory action is being deferred on significant economic impact on a We have examined the impacts of the six active ingredients that were substantial number of small entities. final rule under Executive Order 12866, addressed in the health care antiseptic This analysis, together with other Executive Order 13563, Executive Order proposed rule: Benzalkonium chloride, relevant sections of this document, 13771, the Regulatory Flexibility Act (5 benzethonium chloride, chloroxylenol, serves as the Regulatory Flexibility U.S.C. 601–612), and the Unfunded ethyl alcohol, isopropyl alcohol, and Analysis, as required under the Mandates Reform Act of 1995 (Pub. L. povidone-iodine. This final rule also Regulatory Flexibility Act. 104–4). Executive Orders 12866 and addresses the eligibility of three active We have developed a comprehensive 13563 direct us to assess all costs and ingredients—alcohol (ethyl alcohol, see Economic Analysis of Impacts that benefits of available regulatory section V.C.3), benzethonium chloride, assesses the impacts of the final rule. alternatives and, when regulation is and chlorhexidine gluconate—and finds The full analysis of economic impacts is necessary, to select regulatory that these three active ingredients are available in docket FDA–2015–N–0101 approaches that maximize net benefits ineligible for evaluation under the OTC (Ref. 78) and at https://www.fda.gov/ (including potential economic, Drug Review for certain health care AboutFDA/ReportsManualsForms/ environmental, public health and safety, antiseptic uses (see section IV.D.1, table Reports/EconomicAnalyses/default.htm.

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TABLE 5—EXECUTIVE ORDER 13771 SUMMARY TABLE [In $ millions 2016 dollars, over an infinite time horizon]

Primary Lower bound Upper bound (7%) (7%) (7%)

Present value of costs ...... $17.19 $8.68 $29.47 Present Value of Cost Savings ...... Present Value of Net Costs ...... 17.19 8.68 29.47 Annualized Costs ...... 1.20 0.61 2.06 Annualized Cost Savings ...... Annualized Net Costs ...... 1.20 0.61 2.06

IX. Paperwork Reduction Act of 1995 environmental assessment nor an provision or there is some other clear environmental impact statement is evidence that the Congress intended This final rule contains no collection of information. Therefore, clearance by required. preemption of State law, or where the exercise of State authority conflicts with OMB under the Paperwork Reduction XI. Federalism Act of 1995 is not required. the exercise of Federal authority under We have analyzed this final rule in the Federal statute.’’ The sole statutory X. Analysis of Environmental Impact accordance with the principles set forth provision giving preemptive effect to the We have determined under 21 CFR in Executive Order 13132. Section 4(a) final rule is section 751 of the FD&C Act 25.31(a) that this action is of a type that of the Executive order requires agencies (21 U.S.C. 379r). We have complied does not individually or cumulatively to ‘‘construe . . . a Federal statute to with all of the applicable requirements have a significant effect on the human preempt State law only where the under the Executive order and have environment. Therefore, neither an statute contains an express preemption determined that the preemptive effects

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of this rule are consistent with 1989. Available at http://www.ncbi. 20170404152730/https://www.fda.gov/ Executive Order 13132. nlm.nih.gov/pubmed/2642372. AdvisoryCommittees/Committees 10. FDA Deferral Letter for Benzalkonium MeetingMaterials/Drugs/Nonprescription XII. References Chloride in Health Care Antiseptics on DrugsAdvisoryCommittee/ The following references are on January 19, 2017. Available at https:// ucm410287.htm. www.regulations.gov/document?D=FDA- 22. International Council for Harmonisation display at the office of the Dockets 2015-N-0101-1321. of Technical Requirements for Management Staff (see ADDRESSES) and 11. FDA Deferral Letter for Benzethonium Pharmaceuticals for Human Use, are available for viewing by interested Chloride in Health Care Antiseptics on Guideline for Industry. The Need for persons between 9 a.m. and 4 p.m., January 19, 2017. Available at https:// Carcinogenicity Studies of Monday through Friday; they are also www.regulations.gov/document?D=FDA- Pharmaceuticals. Available at http:// available electronically at https:// 2015-N-0101-1322. www.fda.gov/downloads/drugs/.../ www.regulations.gov. FDA has verified 12. FDA Deferral Letter for Chloroxylenol in guidances/ucm074911.pdf. Health Care Antiseptics on January 19, 23. Food and Drug Administration, Draft all website addresses, as of the date of Guidance for Industry. Endocrine this document publishes in the Federal 2017. Available at https://www. regulations.gov/document?D=FDA-2015- Disruption Potential of Drugs: Register, but websites are subject to N-0101-1323. Nonclinical Evaluation. Available at change over time. 13. FDA Deferral Letter for Ethyl Alcohol in https://www.federalregister.gov/ 1. Transcript of the January 22, 1997, Joint Health Care Antiseptics on January 19, documents/2013/09/20/2013-22864/ Meeting of the Nonprescription Drugs 2017. 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Iodine Solutions, Journal of Hospital Bacteria Causing Urinary Tract Infection Antiseptics; Topical Antimicrobial Drug Infection, 6(Supp A): p. 59–66, 1985. in Spinal Cord Injured Patients, Products for Over-the-Counter Human Available at http://www.ncbi.nlm.nih. Paraplegia, 19(1): p. 50–58, 1981. Use. Available at http://www.fda.gov/ gov/pubmed/2860177. Available at https://www.ncbi.nlm.nih. AboutFDA/ReportsManualsForms/ 60. Yasuda, T., et al., Comparison of gov/pubmed/7220061. Reports/EconomicAnalyses/default.htm. Bactericidal Activities of Various 70. 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Shi, G.S., et al., Prevalence of Antiseptic- Drug, and Cosmetic Act and under Povidone-Iodine and Chlorhexidine Resistance Genes in Staphylococci authority delegated to the Commissioner Against Methicillin-Resistant Isolated from Orthokeratology Lens and of Food and Drugs, 21 CFR part 310 is Staphylococcus aureus, Surgical Spectacle Wearers in Hong Kong, amended as follows: Research Communications, 5(4): p. 313– Investigative Ophthalmology and Visual 14, 1989. Available at http://www. Science, 56(5): p. 3069–74, 2015. PART 310—NEW DRUGS embase.com/search/results?subaction= Available at https://www.ncbi.nlm.nih. viewrecord&from=export&id= gov/pubmed/?term=25788652. ■ 1. The authority citation for part 310 L19121090. 72. Lambert, R.J., Comparative Analysis of continues to read as follows: 62. Barry, A.L., et al., Lack of Effect of Antibiotic and Antimicrobial Biocide Authority: 21 U.S.C. 321, 331, 351, 352, Antibiotic Resistance on Susceptibility Susceptibility Data in Clinical Isolates of 353, 355, 360b–360f, 360j, 360hh–360ss, of Microorganisms to Chlorhexidine Methicillin-Sensitive Staphylococcus 361(a), 371, 374, 375, 379e, 379k–l; 42 U.S.C. Gluconate or Povidone Iodine, European aureus, Methicillin-Resistant 216, 241, 242(a), 262. Journal of Clinical Microbiology and Staphylococcus aureus and Infectious Diseases, 18(12): p. 920–21, Pseudomonas aeruginosa between 1989 ■ 2. Amend § 310.545 as follows: 1999. Available at https://www.ncbi.nlm. and 2000, Journal of Applied ■ a. Add reserved paragraphs (a)(27)(v), nih.gov/pubmed/?term=10691210. Microbiology, 97(4): p. 699–711, 2004. (vii), and (ix); 63. Rikimaru, T., et al., Efficacy of Common Available at https://www.ncbi.nlm.nih. ■ b. Add paragraphs (a)(27)(vi), (viii), Antiseptics Against Multidrug-Resistant gov/pubmed/?term=15357719. and (x); Mycobacterium tuberculosis, 73. Morrissey, I., et al., Evaluation of ■ c. In paragraph (d) introductory text, International Journal of Tuberculosis Epidemiological Cut-Off Values Indicates remove ‘‘(d)(41)’’ and in its place add and Lung Disease, 6(9): p. 763–70, 2002. That Biocide Resistant Subpopulations Are Uncommon in Natural Isolates of ‘‘(42)’’; and Available at https://www.ncbi.nlm. ■ nih.gov/pubmed/?term=12234131. Clinically-Relevant Microorganisms, d. Add paragraph (d)(42). 64. Sakuragi, T., et al., Bactericidal Activity PLoS One, 9(1): p. 86669, 2014. The additions read as follows: of Skin Disinfectants on Methicillin- Available at http://www.ncbi.nlm. § 310.545 Drug products containing Resistant Staphylococcus aureus, nih.gov/pubmed/24466194. certain active ingredients offered over-the- Anesthesia and Analgesia, 81(3): p. 555– 74. Copitch, J.L., et al., Prevalence of counter (OTC) for certain uses. 58, 1995. Available at http://www.ncbi. Decreased Susceptibility to Triclosan in nlm.nih.gov/pubmed/7653822. Salmonella enterica Isolates from (a) * * * 65. Sanchez, P., et al., The Biocide Triclosan Animals and Humans and Association (27) * * * Selects Stenotrophomonas maltophilia with Multiple Drug Resistance, (v) [Reserved] Mutants That Overproduce the SmeDEF International Journal of Antimicrobial (vi) Health care personnel hand wash Multidrug Efflux Pump, Antimicrobial Agents, 36(3): p. 247–51, 2010. Available drug products. Approved as of Agents and Chemotherapy, 49(2): p. at https://www.ncbi.nlm.nih.gov/ December 20, 2018. 781–82, 2005. Available at https:// pubmed/?term=20541914. www.ncbi.nlm.nih.gov/pubmed/?term= 75. Braoudaki, M. and A.C. Hilton, Adaptive Cloflucarban 15673767. Resistance to Biocides in Salmonella Fluorosalan 66. Payne, D.N., et al., Antiseptics: A enterica and Escherichia coli O157 and Hexachlorophene Forgotten Weapon in the Control of Cross-Resistance to Antimicrobial Hexylresorcinol Antibiotic Resistant Bacteria in Hospital Agents, Journal of Clinical Microbiology, Iodine complex (ammonium ether and Community Settings?, Journal of the 42(1): p. 73–78, 2004. Available at sulfate and polyoxyethylene sorbitan Royal Society of Health, 118(1): p. 18–22, https://www.ncbi.nlm.nih.gov/pubmed/ monolaurate) 1998. Available at https://www.ncbi. ?term=14715734. Iodine complex (phosphate ester of nlm.nih.gov/pubmed/?term=9724934. 76. Langsrud, S., et al., Cross-Resistance to alkylaryloxy polyethylene glycol) 67. Oggioni, M.R., et al., Significant Antibiotics of Escherichia coli Adapted Methylbenzethonium chloride Differences Characterize the Correlation to Benzalkonium Chloride or Exposed to Coefficients Between Biocide and Stress-Inducers, Journal of Applied Nonylphenoxypoly (ethyleneoxy) Antibiotic Susceptibility Profiles in Microbiology, 96(1): p. 201–08, 2004. ethanoliodine Staphylococcus aureus, Current Available at https:// Phenol Pharmaceutical Design, 21(16): p. 2054– www.ncbi.nlm.nih.gov/pubmed/ Poloxamer-iodine complex 57, 2015. Available at https://www.ncbi. ?term=14678175. Secondary amyltricresols nlm.nih.gov/pubmed/?term=25760337. 77. Joynson, J.A., et al., Adaptive Resistance Sodium oxychlorosene 68. Coelho, J.R., et al., The Use of Machine to Benzalkonium Chloride, Amikacin Tribromsalan Learning Methodologies to Analyse and Tobramycin: The Effect on Triclocarban Antibiotic and Biocide Susceptibility in Susceptibility to Other Antimicrobials, Triclosan Staphylococcus aureus, PLoS One, 8(2): Journal of Applied Microbiology, 93(1): Undecoylium chloride iodine complex p. 1, 2013. Available at https:// p. 96–107, 2002. Available at https:// www.ncbi.nlm.nih.gov/pubmed/?term= www.ncbi.nlm.nih.gov/pubmed/ (vii) [Reserved] 23431361. ?term=12067378. (viii) Surgical hand scrub drug 69. Stickler, D.J., et al., Antiseptic and 78. FDA Regulatory Impact Analysis, Safety products. Approved as of December 20, Antibiotic Resistance in Gram-Negative and Effectiveness for Health Care 2018.

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Cloflucarban (x) Patient antiseptic skin preparation Triclosan Fluorosalan drug products. Approved as of Triple dye Hexachlorophene December 20, 2018. Undecoylium chloride iodine complex Hexylresorcinol Cloflucarban Combination of calomel, oxyquinoline Iodine complex (ammonium ether Fluorosalan sulfate and polyoxyethylene sorbitan benzoate, triethanolamine, and Hexachlorophene phenol derivative monolaurate) Hexylresorcinol Iodine complex (phosphate ester of Iodine complex (phosphate ester of Combination of mercufenol chloride alkylaryloxy polyethylene glycol) alkylaryloxy polyethylene glycol) and secondary amyltricresols in 50 Methylbenzethonium chloride Iodine tincture (USP) percent alcohol Nonylphenoxypoly (ethyleneoxy) Iodine topical solution (USP) * * * * * ethanoliodine Mercufenol chloride (d) * * * Phenol Methylbenzethonium chloride (42) December 20, 2018, for products Poloxamer-iodine complex Nonylphenoxypoly (ethyleneoxy) subject to paragraphs (a)(27)(vi) through Secondary amyltricresols ethanoliodine (x) of this section. Sodium oxychlorosene Phenol Dated: December 14, 2017. Tribromsalan Poloxamer-iodine complex Triclocarban Secondary amyltricresols Leslie Kux, Triclosan Sodium oxychlorosene Associate Commissioner for Policy. Undecoylium chloride iodine complex Tribromsalan [FR Doc. 2017–27317 Filed 12–19–17; 8:45 am] (ix) [Reserved] Triclocarban BILLING CODE 4164–01–P

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