August 14, 2019 Docket Nos. FDA-1975-N-0012

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration Silver Spring MD 20993

August 14, 2019

Docket Nos. FDA-1975-N-0012; FDA-2015-N-0101; and FDA-2016-N-0124

American Cleaning Institute Attention: Richard Sedlak Executive Vice President, Technical and International Affairs 1331 L Street, NW, Suite 650 Washington, DC 20005

Re: Benzalkonium Chloride, Benzethonium Chloride, Chloroxylenol, Ethanol, and Povidone- Iodine

Dear Mr. Sedlak:

This letter responds to American Cleaning Institute’s (ACI’s) March 12, 2019 request: (1) for a renewal of the extension of the deferral from final rulemaking under the OTC Drug Review on benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, and povidone-iodine for use in nonprescription (often referred to as over-the-counter or OTC) consumer antiseptic wash, health care antiseptic, and consumer antiseptic rub drug products.

In March 2016, FDA issued letters granting requests to defer three active ingredients—benzalkonium chloride, benzethonium chloride, and chloroxylenol—from inclusion in the final rulemaking for the December 2013 proposed rule for OTC consumer antiseptic washes (78 FR 76444). Similarly, in January 2017, FDA issued letters granting requests to defer six active ingredients—benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, povidone-iodine, and isopropyl alcohol—from inclusion in the final rulemaking for the May 2015 proposed rule for OTC health care antiseptics (80 FR 25166). In October 2017, FDA issued letters granting requests to defer three active ingredients— benzalkonium chloride, ethanol, and isopropyl alcohol—from inclusion in the final rulemaking for the June 2016 proposed rule for OTC consumer rub antiseptics (81 FR 42912).

In April 2018, FDA granted an extension to defer final rulemaking on these five active ingredients-- benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, and povidone-iodine--under the antiseptic rulemakings, and granted ACI’s request to harmonize into a single document and reporting cycle the timing for deferrals of these five active ingredients among the various antiseptic rulemakings for which it has requested deferrals.

As explained in each of the deferral letters, FDA deferred inclusion of these active ingredients from each of the respective rulemakings for one year, subject to renewal, to allow more time for completion of the studies necessary to demonstrate safety and effectiveness. FDA also stated, however, that “if no such studies have been commenced, or if the studies in progress do not appear, in FDA’s judgment, to be productive, the agency expects that it will proceed to rulemaking for [the] ingredient[s] after [the] initial deferral[s].”

ACI submitted its statements of intent to fill the safety and effectiveness data gaps for benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, and povidone-iodine under the antiseptic rulemaking proceedings for use in OTC consumer antiseptic washes, consumer antiseptic rubs, and health care antiseptic products, for certain specified indications. To date, ACI has submitted multiple reports demonstrating its ongoing progress in conducting the necessary safety and efficacy studies (see April 12, 2018 FDA Extension Deferral Letter). On March 12, 2019, ACI submitted its most recent progress report and provided reference to the following updated information in support of its progress in fulfilling the data gaps:

(1) A February 15, 2019 final report (#150941-202) for the active ingredients benzalkonium chloride, benzethonium chloride, chloroxylenol, povidone-iodine and ethanol entitled “Determination of the Minimum Inhibitory Concentrations (MIC) and Minimum Bacterial Concentrations (MBC) of Five Test Materials” (currently pending FDA’s feedback);

(2) A February 26, 2019 response to comments and questions contained in FDA’s Advice letter dated July 5, 2018 regarding the time-kill study final report (#150940-201) for the active ingredients benzalkonium chloride, benzethonium chloride, chloroxylenol, and ethanol;

(3) A final report on the ethanol efficacy study submitted as part of the Briefing Package for the March 1, 2018 Meeting with FDA. A draft pivotal protocol (applicable to ethanol for health care personnel and consumer hand rub) has been developed and its implementation is currently pending the identification of a second clinical laboratory qualified to conduct the study. The final protocol will be submitted to FDA prior to study start-up;

(4) Research conducted to: 1) assess whether there are significant dermal absorption differences among the marketed formulas of consumer antiseptic hand wash products, and 2) identify a product type having the greatest dermal penetration of the actives benzalkonium chloride and benzethonium chloride in liquid, bar, and foaming formulations. Consequently, final reports (#39290 and #39479) were submitted for in vitro dermal penetration studies of benzalkonium chloride and benzethonium chloride for the Feedback Meeting on May 9, 2018. This information will be used to define the number of hand hygiene events in a pilot maximal use trial

(MUsT) for health care antiseptic products containing benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol and povidone-iodine;

(5) A draft pilot MUsT study protocol (“A Pilot Maximal Use Study to Measure the Systemic Absorption of Benzalkonium Chloride (BAC) After Exaggerated Use of the Antimicrobial Soap on Intact Skin in Healthy Volunteers”) submitted for FDA review and feedback at the meeting on May 9, 2018;

(6) A search effort seeking qualification of a second laboratory to conduct the full range of pivotal in vivo studies for benzalkonium chloride, chloroxylenol, ethanol and povidone-iodine. Performance evaluation at candidate laboratories in 2018 failed to identify a second laboratory qualified to conduct the studies. Additional efforts are continuing to address/correct issues identified during qualification audits and to identify additional candidate laboratories;

(7) A final report on the observational studies (for benzalkonium chloride and benzethonium chloride) submitted for FDA’s review under the Feedback Meeting of May 9, 2018 in regard to the MUsT program. This information will be used to define the maximum number of washes in a proposed pilot MUsT for consumer antiseptic hand wash products containing benzalkonium chloride, benzethonium chloride, and chloroxylenol.

(8) A meeting with FDA on August 6, 2018 to obtain review feedback on the Enterotoxigenic Escherichia coli (ETEC; strain H10407) (ETEC) challenge study protocol (proposed foodborne induction model for consumer hand wash products) and the Skin Infection Model for consumer hand wash products, focusing on clinical outcome study design elements based on FDA’s April 3, 2017 Advice Letter and follow-up studies. These studies would generate data for benzalkonium chloride, benzethonium chloride, and chloroxylenol;

(9) A revised ethanol maximal usage trial (MUsT) protocol (supporting formulation permeation data and additional information on bioanalytical method development submitted to FDA for review on July 13, 2017) to address comments received from FDA in an Advice letter dated August 6, 2018.

FDA has reviewed the information that ACI has submitted thus far in support of its progress to demonstrate safety and effectiveness for benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, and povidone-iodine. Based on this review, FDA grants another extension to defer final rulemaking on these five active ingredients under the antiseptic rulemakings. The extension to defer final rulemaking on the five active ingredients shall be for one year from the date of this letter, subject to renewal. A report describing ACI’s specific progress on all ongoing studies for these five active ingredients is to be submitted to FDA by July14, 2020.

We note that ACI’s March 2019 progress report is missing the status and milestones for some of the in vivo efficacy studies for the active ingredients povidone iodine and benzethonium chloride for certain health care antiseptic indications. Although ACI has indicated that reduced funding and limitations in laboratory testing capacity have made it difficult to identify a reliable time schedule for these studies, an estimated timeline is necessary for awareness and a consistent assessment of expectations and is to be provided. In addition, ACI has indicated that it will no longer be working on studies for the health care

3 personnel hand wash indication for the active ingredient benzethonium chloride because of reduced funding. As we have stated in previous correspondence, in order for FDA to continue to grant deferrals of final rulemaking for the respective active ingredients, it is important for sponsors to demonstrate that progress has been made for each study. This includes a commitment to conduct the applicable studies within a reasonable timetable. FDA requests to meet with ACI to discuss these issues in more detail. The Agency acknowledges ACI’s commitment to generating the necessary safety and effectiveness data, and understands that ACI is also requesting “assurances for longer term market access” in the form of a multiyear deferral. FDA declines to grant a multiyear deferral, but assuming ACI continues to make progress in its ongoing studies, the Agency anticipates that future extensions of the deferral may be granted. Although FDA remains fully committed to working with sponsors throughout the extent of this process, the Agency believes that the nature of the development of the necessary safety and effectiveness data requires FDA to review and evaluate the information on a step-by-step basis. For example, the results of the maximal usage study trial (MUsT), when completed, will inform prospective timing, needs, and expectations for subsequent or additional safety studies. Moreover, the review of monograph active ingredients is based not only on the data submitted by the sponsors, but also on peer- reviewed published data, and, thus, the needs and the conditions for completion of safety and effectiveness studies may be assessed and reevaluated as new studies and publications become available.

For the reasons explained above, FDA believes that a one-year deferral extension, subject to renewal, allows the Agency to better assess the actual expectations and continued progress of these studies.

FDA appreciates ACI’s commitment to conducting the necessary safety and effectiveness studies for benzalkonium chloride, benzethonium chloride, chloroxylenol, ethanol, and povidone-iodine. If you have any questions, please call Celia Peacock, Regulatory Project Manager, at (301) 796-4154.

Sincerely,

Theresa Michele, MD Director Division of Nonprescription Drug Products Office of Drug Evaluation IV Center for Drug Evaluation and Research