The FDA has published a Federal Register Notice announcing the reopening of the administrative record on the Tentative Final Monograph (TFM) for Topical Antimicrobial Drug Products for Over-the-Counter Human Use. The Agency has taken this somewhat unusual position due to an overabundance of caution regarding the safety and effectiveness of such over-the–counter (OTC) products. FDA notes that in no way does it believe that there may be a problem of safety or effectiveness of existing marketed products; however, the Agency notes that, over the course of time, new scientific methods and concerns make such changes reasonable to assure the monograph conditions are reflecting the current state of knowledge.
The TFM was first published in 1994 and, since then, the FDA’s concern about increased microbial resistance, as well as new methods capable of measuring the amount of absorption of the monograph ingredients was incentive for the Agency to reopen the administrative record. FDA is also proposing that “health care antiseptic active ingredients have in vitro data characterizing the ingredient’s antimicrobial properties and in vivo clinical simulation studies showing that specified log reductions in the amount of certain bacteria are achieved using the ingredient.” These changes are based on information that the Agency has received in comments to the TFM and on new information available to the FDA.
In terms of new information for effectiveness, the Agency notes:
A determination that a drug product containing a particular active ingredient would be generally recognized as effective (GRAE) for a particular intended use requires consideration of the benefit-to-risk ratio for the drug for that use. New information on potential risks posed by the use of certain health care antiseptic products, as well as input from the Nonprescription Drugs Advisory Committee (NDAC) that met in March 2005 (the March 2005 NDAC), has prompted us to reevaluate the data needed for classifying health care antiseptic active ingredients as GRAE (see new information described in the Safety section of this summary). We continue to propose the use of surrogate endpoints (bacterial log reductions) as a demonstration of effectiveness for health care antiseptics combined with in vitro testing to characterize the antimicrobial activity of the ingredient. However, the log reductions required for the demonstration of effectiveness for health care antiseptics have been revised based on the recommendations of the March 2005 NDAC, comments received after the 1994 TFM, and other information that FDA reviewed.
In terms of Safety, the Agency notes:
Several important scientific developments that affect the safety evaluation of these ingredients have occurred since FDA’s 1994 evaluation of the safety of health care antiseptic active ingredients under the OTC Drug Review. Improved analytical methods now exist that can detect and more accurately measure these active ingredients at lower levels in the bloodstream and tissue. Consequently, we now know that, at least for certain health care antiseptic ingredients, 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. Currently, the significance of this new information is not known and we are unaware of any information that would lead us to conclude that any health care antiseptic active ingredient is unsafe (other than those that we proposed to be Category II in the 1994 TFM). The benefits of any active ingredient will need to be weighed against its risks once both the effectiveness and safety have been better characterized to determine GRAS/GRAE status.
The data FDA will be requiring to further demonstrate and confirm the safety of these products fall into four broad categories:
(1) Human safety studies described in current FDA guidance (e.g., maximal use trials or MUsT)
(2) nonclinical safety studies described in current FDA guidance (e.g., developmental and reproductive toxicity studies and carcinogenicity studies)
(3) data to characterize potential hormonal effects, and
(4) data to evaluate the development of antimicrobial resistance.
There are a number of active ingredients cited in the TFM and the Agency will be looking for additional data as described further in the Federal register Notice (here) so be certain to review the entire Notice along with the timeframes for which the FDA expectations should be met, to assure continued availability of the products subject to the TFM, and that the FDA has all available information to assure that the products continue to be recognized as safe and effective. Again, the Agency emphasizes that there is no reason to believe that any of the products present a safety or efficacy problem, but that the Agency wants the additional information and data to help it reconfirm the conclusions reached in the TFM and for its final monograph decisions to be based on the most current scientifically valid assessment.