Since the 1970s, FDA approval of a new drug requires an evaluation of the in vivo bioavailability of the drug, as part of the drug’s safety assessment. Bioavailability refers to the fraction of the administered drug dose that reaches the bloodstream and the rate at which it reaches the bloodstream. Although this regulatory requirement has been in place for decades, clinical trials to evaluate topical drugs for bioavailability have been difficult to conduct, primarily due to the limited bioanalytical methods available to measure low concentrations of a drug in the blood. Also, these safety assessments were further encumbered by a lack of standardized study design and the general assumption that a drug’s absorption through the skin was negligible compared to a drug systemically administered.
Advancements in the sensitivity of bioanalytical methods have made bioavailability studies for topical drugs more achievable. Consequently, new data are suggesting that exposure to some topical drugs results in greater absorption than previously thought. To address this concern, in the late 1990s the FDA developed the Maximal Usage Trial (MUsT) to standardize a study design for measuring the bioavailability of topically administered drugs.
The intent of the MUsT is to simulate the high end of the expected usage pattern of a topical product as a means to evaluate absorption under maximal use. For example, to assess the absorption of an antiseptic hand sanitizer designed for health care personnel in a hospital setting, a MUsT might be conducted with subjects rubbing their hands with the product 50 times per day for multiple days. Blood samples from the subjects would be collected periodically throughout the duration of the study to measure the product concentration that reached the blood. The assumption of this study is that the real-use maximum exposure to the product would result in a maximum concentration in the blood, allowing an accurate safety assessment of the systemic absorption.
The MUsT outlined by the FDA considers important factors that affect the absorption of a topical product and have included these in the suggested study design. Examples are appropriate subject populations, frequency, and duration of dosing, the concentration of the product, the surface area covered by one product application, and the method of product application. Additionally, a validated and sensitive bioanalytical assay is a key requirement.
In FDA’s December 20, 2017, Final Rule for Safety and Effectiveness of Health Care Antiseptics: Topical Antimicrobial Drug Products for Over-the-Counter Human Use, MUsT Studies are now required as additional data to meet current safety standards for all health care topical antiseptics.
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