FDA Proposes an “Amendment of the Tentative Final Monograph (TFM) on Health Care Antiseptic Drug Products” to Address Data Gaps Regarding Effectiveness and Safety

May 4, 2015

By Riëtte van Laack

Continuing its broad application of  the consent decree in the action by the National Resource Defense Council against FDA (see our previous post here), FDA issued a proposal to amend the Tentative Final Monograph for Topical Antimicrobial Drug Products for Over-the-Counter Human Use. At this stage, FDA proposes to amend the 1994 TFM for the over-the counter (OTC) health care antiseptic drug products.  These health care antiseptic products include health care personnel hand washes, health care personnel hand rubs, surgical hand scrubs, surgical hand rubs, and patient preoperative skin preparations.  FDA previously proposed to amend the portion of the 1994 TFM that applies to consumer antiseptics.

Referring to  modern standards for effectiveness and safety, FDA proposes to reclassify all active ingredients that in 1994 were classified as category I (i.e., shown to be safe and effective) or category III (i.e., additional data are needed for safety or effectiveness), as category III for both safety and effectiveness.  In short, FDA has determined that it currently has insufficient data to conclude that any of the health care antimicrobial active ingredients are generally recognized as safe (GRAS) and effective (GRAE) under FDA’s updated standards.  Unless additional data are submitted to support GRAS and GRAE under the updated standards, FDA will declare them non-monograph ingredients in the final monograph.

In contrast to the Agency’s tone in announcing the proposal regarding consumer antiseptics [link to dec. 2013 blog post], FDA this time stresses that health care professionals should continue to use the current products while additional safety and efficacy data are being obtained.  For example, in the press release, FDA states that “[t]he FDA’s request for more safety and effectiveness data for health care antiseptic active ingredients should not be taken to mean the FDA believes that these products are ineffective or unsafe.”

Also in contrast to the consumer antiseptics proposal, the Agency does not propose requiring clinical data to support GRAE status for the health care antiseptic products.  Instead, FDA continues to propose the use of surrogate endpoints (bacterial log reductions) combined with in vitro testing to characterize the antimicrobial activity of the ingredient as evidence of the effectiveness for health care antiseptics.  However, the log reduction standards have been revised to require an instant reduction upon a one-time use/application.  (See table below).  These updated criteria are based on published literature and have been used in review of antiseptics approved under the NDA process.

Table: Clinical Simulation Testing Bacterial Log Reduction Effectiveness Criteria in This Proposed Rule and in the 1994 TFM 


1994 TFM

Proposed Rule

Health care personnel hand wash or health care personnel hand rub


  • reduction of  2 log on each hand within 5 minutes after the first wash, and
  • reduction of 3 log on each hand within 5 minutes after the tenth wash.
  • reduction of  2.5 log on each hand within 5 minutes after a single wash or rub

Surgical hand scrub of surgical hand rub

  • reduction of 1 log on each hand within 1 minute after the first wash on day 1,
  • does not exceed baseline at 6 hours on day 1, and
  • reduction of  2 log on each hand within 1 minutes after the last wash on day 2, and
  • reduction of 3 log on each hand within 1 minute after the last wash on day 5.
  •  Reduction of 2 log on each hand within 1 minute after a single wash or rub, and
  • Does not exceed baseline at 6 hours.

Patient preoperative skin preparation

  • reduction of 2 log per square centimeter on abdominal site within 10 minutes after use, and
  • reduction of 3 log per square centimeter on groin site within 10 minutes after use, and
  • does not exceed baseline at 6 hours.
  •  reduction of 2 log per square centimeter on abdominal site within 30 seconds after use, and
  • reduction of 3 log per square centimeter on groin site within 30 seconds after use, and
  • does not exceed baseline at 6 hours.

Because this standard is different from what FDA proposed in 1994, the Agency has no evidence that any of the ingredients meet the updated standard. 

As discussed in the proposal regarding consumer antiseptic drug products, several scientific developments that affect the safety evaluation of antimicrobial ingredients have occurred since FDA’s 1994 evaluation of the safety of health care antiseptic active ingredients.  Not surprisingly, FDA does not have data to address some of these concerns.  Among others, FDA now requires data regarding antimicrobial resistance, human safety studies (e.g., maximal use trials), nonclinical safety studies (e.g., developmental and reproductive toxicity studies and carcinogenicity studies), and data to characterize potential hormonal effects.  For each category III health care antiseptic ingredient, FDA discusses what data are available and what data are missing.  For example, for alcohol, only data regarding human pharmacokinetics are incomplete, whereas for benzalkonium chloride, data regarding human and animal pharmacokinetics, dermal carcinogenicity, reproductive toxicity, and hormonal effects, are missing.

Comments are due October 28, 2015.  FDA explains that it provides a longer comments period (i.e., 180 days) because of the complexity of the proposed rule.  In addition, new data or information may be submitted to the docket via regulations.gov until May 1, 2016, and comments on any new data or information may then be submitted for an additional 60 days.  The Agency also states that it will consider requests to defer further rulemaking with respect to a specific active ingredient so that additional new safety or effectiveness data can be submitted.  The Agency does not commit to a date for the final rule, although the consent order sets a date for the publication of the final monograph on triclosan of January 15, 2018.  Because the proposed rule only addresses the GRAE and GRAS status of active ingredients and no other amendments to the TFM, e.g., tests for the final product, finalizing the TFM will involve further amendments.