FDA Announces Availability of a Final Guidance, “Maximal Usage Trials for Topically Applied Active Ingredients Being Considered for Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations”

FDA Announces Availability of a Final Guidance, “Maximal Usage Trials for Topically Applied Active Ingredients Being Considered for Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations”

On May 9, 2019, the U.S. Food and Drug Administration (FDA) announced the availability of a final guidance for industry entitled "Maximal Usage Trials for Topically Applied Active Ingredients Being Considered for Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations." 

A Maximal Usage Trial (MUsT) is a standard approach to assess the in vivo bioavailability of topical drug products intended for local therapeutic effects. Information from a MUsT can help identify the potential for systemic exposure to a topically applied active ingredient and inform an FDA determination of whether additional safety data are needed to support a finding that a topical over-the-counter (OTC) drug containing that active ingredient is generally recognized as safe and effective (GRASE) for its intended use. This guidance outlines FDA’s recommendations for designing and conducting a MUsT for this purpose, including critical study elements, data analysis, and considerations for special topic areas (e.g., pediatrics, geriatrics).  

A critical safety consideration for topical drugs is whether applying the drug to the skin results in dermal penetration and systemic exposure to the active ingredient, and, if so, to what extent. This information helps identify potential safety concerns and helps determine whether an adequate safety margin exists for an active ingredient to be included in a relevant OTC monograph. To assess an active ingredient proposed for use in any topical drug product under the OTC monograph system, the underlying goal of the MUsT is to evaluate systemic exposure levels under conditions relevant to real-world use that maximize the potential for dermal absorption. Accordingly, the conduct of a MUsT should be consistent with maximal use of the product as specified by existing or anticipated labeling. An example of a MUsT was recently published in the May 6, 2019, Journal of the American Medical Association, in which Matta et al. describe the results of an exploratory MUsT evaluating the systemic absorption of sunscreen active ingredients using four commercially available sunscreen products applied under maximal use conditions.¹ In this pilot study, all four active ingredients tested were absorbed from each formulation tested, demonstrating that absorption of sunscreens is not just a theoretical safety concern.

The FDA recognizes that more than one study design can provide this information and that many factors can influence the specific approach to be used. Study sponsors should seek FDA’s input on the formulations to be tested and other proposed study elements prior to conducting the MUsT. 

The "Maximal Usage Trials for Topically Applied Active Ingredients Being Considered for Inclusion in an Over-the-Counter Monograph: Study Elements and Considerations" final guidance is available at https://go.usa.gov/xmPKD. Please refer to the final guidance for more details. This guidance represents the current thinking of the FDA on this topic. It does not establish any rights for any person and is not binding on FDA or the public. An alternative approach can be considered if it satisfies the requirements of the applicable statutes and regulations. 

1. Matta MK, Zusterzeel R, Pilli NR, et al. Effect of sunscreen application under maximal use conditions on plasma concentration of sunscreen active ingredients: a randomized clinical trial [published May 6, 2019]. JAMA. doi:10.1001/jama.2019.5586. https://jamanetwork.com/journals/jama/fullarticle/2733085