More GRASE Time For 6 OTC Antiseptic Ingredients But 24 Flushed In Final Rule

An FDA final rule rejects generally regarded as safe and effective status for 24 OTC monograph antiseptic ingredients regarding products intended for use by health care professionals in hospitals or similar venues. However, six ingredients on which FDA deferred its decision also are used in consumer antiseptic washes, which GRASE decisions pending in separate rulemakings.

OTC antiseptic product firms are making the most of a recent FDA rulemaking that removes 24 ingredients from approval for use under a monograph by focusing on six substances that remain available but face potential exclusion.

A final rule FDA published in December 2017 applies only the generally regarded as safe and effective (GRASE) status for to antiseptic ingredients in products intended for use by health care professionals in hospitals or similar venues. Effective Dec. 20, 2018, the ingredients no longer will be considered GRASE in formulations for health care personnel hand washes and rubs, surgical hand scrubs and rubs and patient antiseptic skin preparations (see list below). Antiseptic products formulated with any of the ingredients will need pre-market approval in FDA's new drug application process.

No timeline for a rulemaking is set for determining whether the six deferred ingredients will be included in the OTC antiseptic ingredients monograph.

"The monograph or non-monograph status of these six ingredients will be addressed, either after completion and analysis of ongoing studies to address the safety and effectiveness data gaps of these ingredients or at a later date, if these studies are not completed,” FDA stated in the rule.

The rule finalizes a 1994 tentative final monograph for OTC antiseptics, a rare accomplishment for FDA's monograph system which is the regulatory pathway for making the majority of nonprescription drug ingredients available in the US. Congress is considering legislation to streamline the monograph process and establish a user fee program to pay for FDA's work in the system, though lawmakers passed on a chance to include the changes in a bill they passed in 2017 to reauthorize the agency's existing drug and medical device user fee programs. (Also see "Senate OTC Monograph Bill Boosts Industry Hopes For Passage This Year" - Pink Sheet, 6 Feb, 2018.)

While focused strictly on products used by health care providers, the final rule explicitly overlaps with separate rulemakings by FDA's Center for Drug Evaluation and Research on antiseptic wash products marketed to consumers because the six deferred substances are common in consumer antiseptics.

The monograph status of three of the deferred ingredients – povidone-iodine, isopropyl alcohol and benzalkonium chloride – also is deferred in a separate CDER rulemaking for consumer hand rub products intended for use without water – no rinse products. The center set an April, 15, 2019, deadline for approving a final monograph for those products. (Also see "Tests On Professional Antiseptics Could Influence Consumer Hand Wash Market" - Pink Sheet, 8 Feb, 2017.)

Additionally, the status of the three other deferred substances – benzalkonium chloride, benzethonium chloride and chloroxylenol – also is deferred in a third rule published in December 2013 on consumer antiseptic wash-off products.  (Also see "FDA Rule Marks Consumer Antibac Soaps A Possible Endangered Species" - Pink Sheet, 2 Sep, 2016.)

Antiseptic Health Care Ingredients Deemed Not GRASE

FDA's Dec. 19 final rules removes these ingredients from the OTC antispetic monograph for health care use effective Dec. 18, 2018:

• chlorhexidine gluconate
• cloflucarban
• fluorosalan
• hexachlorophene
• hexylresorcinol
• iodophors (iodine-containing ingredients)
• iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate)
• iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
• iodine tincture USP
• iodine topical solution USP
• nonylphenoxypoly (ethyleneoxy) ethanoliodine
• poloxamer-iodine complex
• undecoylium chloride iodine complex
• mercufenol chloride
• methybenzethonium chloride
• phenol
• secondary amyltricresols
• sodium oxychlorosene
• tribromsalan
• triclocarban
• triclosan
• triple dye
• combination of calomel, oxyquinoline benzoate, triethanolamine and phenol derivative
• combination of mercufenol chloride and secondary amyltricresols in 50% alcohol 

“We are working on data needs for the consumer wash, consumer hand rub and health care rules simultaneously, and in some protocols the protocol will satisfy the data needs across all three rules so we could run tests on multiple actives simultaneously," said Richard Sedlak, an executive with the American Cleaning Institute, a trade association representing the US cleaning product industry.

Results from some tests will be applicable to two of the rules, while others will be good for one, Sedlak, ACI's executive vice president for technical and international affairs, added in an interview. "You will see a variety of study reports coming out and we will be specifying in the submissions the rule makings they apply to,” he said.

Consent Decree, Systemic Exposure Prompt FDA

FDA's attention to OTC antiseptic monograph ingredients was spurred by a 2013 consent decree to litigation by the National Resources Defense Council that required the agency to publish a triclosan final monograph by Jan. 15, 2018. Instead, the agency used a rulemaking to finalize the monograph for all ingredients for health care antiseptics. (Also see "Consent Decree Orders FDA Action On Triclosan OTC Monographs" - HBW Insight, 9 Dec, 2013.)

Moreover, CDER states in the health care product rule that new data suggest systemic exposure to the active ingredients “is higher than previously thought, and new information about the potential risks from systemic absorption and long-term exposure is now available. New safety information also suggests that widespread antiseptic use could have an impact on the development of bacteria resistant.”

In addition to identifying non-GRASE ingredients, the rule addressed comments and evidence for including three ingredients – alcohol (ethyl alcohol), benzethonium chloride and chlorhexidine gluconate – in certain health care forms as meeting monograph conditions. The agency said alcohol for use as a surgical hand scrub, benzethonium chloride for use as a health care personnel and surgical hand rub and chlorhexidine in health care antiseptics are not eligible for inclusion in a monograph.

Six Deferrals Are Industry Priority

Anticipating the fate of triclosan and the other 23 ingredients, manufacturers did not provide CDER with data to support the use of the substances and has been phasing the ingredients out of products for years, the final rule states, suggesting limited impact on industry. Instead, antiseptic hand wash makers have focused on supporting continued use of the six deferred actives. 

“Ensuring the safety and effectiveness of over-the-counter health care antiseptics has been a priority for the FDA, not only because these products are an important component of infection control strategies in health care settings, but also because of the role these products may play in contributing to antimicrobial resistance,” said FDA Commissioner Scott Gottlieb in a statement published with the rule.

The deferral “doesn’t mean that products containing these six ingredients are ineffective or unsafe,” added Gottlieb. “These antiseptic products remain an important resource in health care settings. Personnel should continue to use these products consistent with infection control guidelines while the additional data are gathered.”

Trio Of OTC Antiseptic Dockets

• FDA–2015–N–0101 (professional): Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Final Rule Dec. 20, 2017
• FDA 2016–N–0124 (consumer no-rinse): Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use ; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,  June 30, 2016
• FDA 1975–N–0012 (consumer wash off): Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record Dec. 17, 2013

ACI members submitted work plans to FDA in support of all the deferred ingredients except for isopropyl alcohol, for which a separate industry group provided a plan. “The agency has received our work plans and they are designed to fill data gaps the agency wants to identify on the health and safety side,” Sedlak said.

The group’s work plan for each of the five ingredients details the safety or efficacy research planned and states the studies' start dates and dates when results will be submitted to FDA, according to comments ACI submitted on povidone-iodine Dec. 15.

“As we told the agency, its multi-year, multi-millions and we’re trying to go in at a pace that the agency feels is acceptable,” Sedlak said. “We are committed to support [these ingredients] and see that they stay on the market.”

For example, to fill effectiveness data gaps for povidone-iodine, ACI said its members in the 2017 fourth quarter initiated an in vitro time-kill study and separately in vitro minimum inhibitory concentration and minimal bactericidal assays. It plans to complete those in the 2018 second quarter and submit results to FDA in the third quarter; a pilot health care hand wash efficacy study will be submitted to FDA in 2018.

To fill safety gaps, industry plans to initiate a bio-analytics clinical study in the second quarter and complete the work in the fourth quarter, ACI says. Additionally, industry will conduct an in vitro dermal penetration study in the 2018 third quarter, planning to complete it in the 2019 first quarter and submit to FDA in the second quarter that year.

Challenges may arise as some of the studies will require “a substantial amount of time” and therefore “some spacing out of sequencing” to learn and to build upon if necessary, he added. Additionally, efficacy testing is often specific to the use of the formula, so in those cases, one test to fill the gaps for the various antiseptic rules will not work, he suggested.

From the editors of the Tan Sheet.