The FDA is proposing that additional safety and effectiveness data are necessary to support a generally recognized as safe and generally recognized as effective (GRAS/GRAE) determination for over-the-counter (OTC) antiseptic rub active ingredients intended for use by consumers. These ingredients are found in consumer antiseptic products used when soap and water are unavailable, and are left on and are not rinsed off with water. The additional data is being requested due to recent scientific developments and changes in use patterns for these products. The Proposed rule, when final, would amend the 1994 tentative final monograph (1994 TFM) (59 FR 31402) for OTC antiseptic drug products (Proposed rule, 81 FR 42911, June 30, 2016).
The FDA uses monographs to set forth conditions under which drugs in each therapeutic class are regarded as GRAS, GRAE, and not misbranded. In the 1994 TFM, these products were referred to as antiseptic hand washes. The Proposed rule now applies to active ingredients used in consumer antiseptic products referred to as rubs, leave-on products, and hand sanitizers, as well as antiseptic wipes. Because of the complexity of this Proposed rule, the FDA is providing an 180-day comment period through December 27, 2016.
Formulation testing and labeling. Because no ingredients currently meet the criteria for a GRAS/GRAE determination in the Proposed rule, the rulemaking does not specifically address requirements for anticipated final formulation testing (i.e., testing the mixture of both active and inactive ingredients proposed for marketing) or labeling. The FDA anticipates that if the Final rule includes any GRAS/GRAE ingredients, labeling will be addressed and may include elements related to application volume and safety labeling for children, including a warning to keep out of reach of children. The FDA anticipates that specific effectiveness claims in labeling will reflect the testing performed in support of these claims.
Antiseptics for health care professionals omitted. On December 17, 2013 (78 FR 76444) (see FDA to require additional data to determine proper use for over-the-counter antiseptic washes) and May 1, 2015 (80 FR 25166) (see FDA proposes getting the bugs out of its over-the-counter antiseptic standards) the FDA proposed conditions under which OTC consumer antiseptic washes and OTC antiseptics intended for use by health care professionals in a hospital setting or other health care situation outside the hospital are GRAS/GRAE. Those antiseptic products are not addressed in this current Proposed rule.
Safety data. Since the FDA’s 1994 evaluation of the safety of these active ingredients, improved analytical methods have been developed that can detect and more accurately measure these active ingredients at lower levels in the bloodstream and tissue. As a result, the FDA now knows that systemic exposure is higher than previously thought, and new information is available about the potential risks from systemic absorption and long-term exposure. New safety information also suggests that widespread antiseptic use could have an impact on the development of bacterial resistance. Finally, the standard battery of tests that were used to determine the safety of drugs has changed over time to incorporate improvements in safety testing.
Based on these developments, the FDA is now proposing that additional safety data are needed for each consumer antiseptic rub active ingredient to support a GRAS classification. The proposed data, which are needed to demonstrate safety for all consumer antiseptic rub active ingredients, fall into two broad categories: (1) human safety studies and (2) nonclinical safety studies. In addition, for one of the consumer antiseptic rub active ingredients (benzalkonium chloride), data to evaluate the development of antimicrobial resistance also is required to demonstrate its safety.
Effectiveness data. A determination that a drug product containing a particular active ingredient would be GRAE for a particular intended use requires consideration of the benefit-to-risk ratio for the drug under the specified conditions of use.
In the Proposed rule, the FDA continues to propose the use of surrogate endpoints (bacterial log reductions) as a demonstration of effectiveness for consumer antiseptic rubs combined with in vitro testing to characterize the antimicrobial activity of the ingredient. However, because the log reductions required for the demonstration of effectiveness for consumer rubs have been revised, the FDA is proposing that the record contain additional log reduction data to demonstrate the effectiveness of consumer rub active ingredients. The FDA is also asking for data and information to be submitted about the impact of product use factors (such as volume of product per application) on efficacy to help inform labeling and requirements for final formulation testing.
Evaluation of active ingredients. In the Proposed rule, three active ingredients are being evaluated for use as a consumer antiseptic rub: (1) alcohol (ethanol or ethyl alcohol), (2) isopropyl alcohol, and (3) benzalkonium chloride.
In the 1994 TFM, alcohol (60 to 95 percent) was proposed to be classified as GRAS/GRAE for use as an antiseptic hand wash, which included products intended to be rinsed off (washes) and those intended to be left on (rubs). Isopropyl alcohol (70 to 91.3 percent) and benzalkonium chloride and were both proposed to be categorized in Category III in the 1994 TFM because of a lack of adequate effectiveness data for use as an antiseptic hand wash. OTC drugs are classified as Category III if the available data are insufficient to classify them as safe and effective, and further testing is required.
In the Proposed rule, the FDA now proposes that alcohol, isopropyl alcohol, and benzalkonium chloride all need additional safety and effectiveness data to support a classification of GRAS/GRAE for consumer antiseptic rub use. If the FDA does not receive sufficient data to support monograph conditions for consumer antiseptic rub products containing these active ingredients, these active ingredients may not be included in the future OTC consumer antiseptic rub final monograph.
However, any consumer antiseptic rub product containing these active ingredients that are not included in a future final monograph could seek approval to market by submitting a new drug application (NDA). After a final monograph is established, the NDA deviations might be submitted for these products under 21 C.F.R. section 330.11, limiting the scope of review necessary to obtain approval.
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