On May 1, 2015, the Food and Drug Administration (FDA) published an amendment to the Tentative Final Monograph (TFM) for Healthcare Antiseptics which will have widespread ramifications for members of the topical antimicrobial industry. The FDA specified new efficacy criteria that are more stringent than the 1994 TFM. A discussion of the new efficacy criteria was presented in the June newsletter. In this newsletter, I discuss the FDA request for data for a variety of new safety studies on the active ingredients covered by the current TFM.
Since the September 2014 Advisory Committee meeting on Healthcare Antiseptics, the FDA has asked for data in support of these new safety criteria in order for a product to achieve GRAS (generally regarded as safe) status:
The FDA considers skin penetration and systemic exposure to the active ingredient as an important safety consideration because of the frequency of application of topical healthcare antiseptics. Limited data have shown that some antiseptic ingredients are absorbed into the skin and thus, it may be necessary to evaluate the effects of long-term dermal and systemic exposure. Consequently, the FDA will require sponsors to conduct a Maximal Usage Trial (MUsT) as part of the clinical pharmacology/bioavailability assessment of a topical product.
Animal pharmacokinetic data (absorption, distribution, metabolism and excretion — ADME) are used to identify toxic systemic exposure levels that can then be correlated with potential human exposure. Toxicokinetics is used to describe the systemic exposure achieved in animals and to correlate the exposure achieved in toxicity studies to toxicological findings, thus determining the relevance of these findings to human clinical safety. Now, the FDA wants animal toxicokinetic studies performed for antiseptic active ingredients because these studies provide a bridge between toxic levels seen in animal studies (e.g. reproductive, genotoxicity and carcinogenicity studies) and potential human adverse events associated with dermal exposure. The toxicokinetic data obtained in animal studies are compared to clinical study data (e.g. MUsT) to obtain a safety margin of drug exposure which is used to project human safety levels.
The FDA generally requires carcinogenicity studies for any drug to be used continuously for at least six months or used intermittently for at least six months, as in the case of some healthcare antiseptics. These studies may assess the potential risks for dermal and systemic tumors associated with an active ingredient. For any chronically applied topical product, Sponsors need to provide an evaluation of dermal carcinogenicity that involves drug application to the skin of mice or rats for 2 years (i.e., lifetime exposure). Now, the FDA asks for DART studies to assess potential effects that exposure to the active ingredient may have on developing offspring throughout gestation and postnatally until sexual maturation, as well as on the reproductive competence of sexually mature male and female animals.
Developmental effects that can be caused by hormonally active compounds can be identified by the designs of general toxicity and DART studies. If any of the toxicity or DART studies show a positive response that is not adequately understood, then additional studies may be needed to fully characterize the potential effects of topical drug exposure on the exposed individuals. While most antiseptic active ingredients have not been tested for these effects, some antiseptic active ingredients, namely triclosan and triclocarban, have shown hormonal effects in animal models.
Since the 1994 TFM was published, antiseptic resistance and the potential for antibiotic cross-resistance have been studied and analyzed. Specifically, triclosan may cause changes in bacterial efflux activity at nonlethal concentrations. However, resistance testing conducted thus far has been limited mainly to human bacterial pathogens. Only limited data exist on the effects of antiseptic exposure on the bacteria that are predominant in the oral cavity, gut, skin flora and the environment. These organisms may contain resistance determinants that are potentially transferable to human pathogens.
It appears that the desire of the FDA to obtain data from many of these studies is based on limited data, particularly reliant upon data from triclosan. Overall, none of the healthcare antiseptic active ingredients meet all the safety standards proposed by the FDA. The types of data that are most frequently lacking include human maximal exposure data and antimicrobial resistance. Both of these types of studies can be conducted here at BioScience Laboratories, should a Sponsor of an active ingredient need to submit such data.
I have now discussed the new efficacy criteria and the new safety criteria that will be required by the FDA for active ingredients in the amendment to the Healthcare Antiseptic TFM to achieve GRAE and GRAS status, respectively. Next month, I will discuss what steps a Sponsor should take with their product as the deadline for comments to the amended TFM approaches.
Contact Dr. Coderre to learn more about product regulation, or contact our sales department to learn more about safety testing.
Peter Coderre, PhD, MBA
Director of Regulatory Affairs