Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an 

Over-The-Counter Monograph, read the guidance:

https://www.fda.gov/media/125080/download

www.fda.gov

What is recommended in this guidance?

The final guidance Maximal Usage Trials for Topical Active Ingredients Being Considered for 

Inclusion in an Over-The-Counter Monograph: Study Elements and Considerations provides 

recommendations on the design and conduct of Maximal Usage Trials (MUsT) to assess 

the in vivo absorption of topical active ingredients under consideration for inclusion in an 

over-the-counter (OTC) monograph.

Are you submitting a topical active ingredient being 

considered for inclusion in an OTC monograph?

FDA recommends MUsT to assess the potential for and extent of systemic exposure by a 

topical active ingredient that occurs as part of the determination of whether an OTC drug 

containing that active ingredient is generally recognized as safe and effective (GRASE) for 

its intended use.

MUsT Can Help Answer the 

Following Questions:

Does the active ingredient have dermal penetration and systemic 

exposure and, if so, to what extent? 

If there is systemic exposure, does the exposure change in 

different populations or conditions?

When considered with other available safety and effectiveness 

data, do the plasma levels support that the ingredient is 

generally recognized as safe and effective under the intended 

conditions of use?

Maximal Usage Trials for Topical Active Ingredients Being Considered for

Inclusion in an Over-The-Counter Monograph: Study Elements and Considerations

Final Guidance
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an OverThe-Counter Monograph, read the guidance: 

https://www.fda.gov/media/125080/download

www.fda.gov

Study Population

and Size

Formulation

Dosage and Application

Sample Collection

& Analytical Testing 

Geriatric & Pediatric

Populations 

MUsT Study Elements and Considerations

The study population should be representative of the population expected to use the 

product. The sample size should be large enough to provide an estimate of the 

maximum exposure considering any potential sources of intersubject and intrasubject 

variability. 

Subjects should be dosed at the highest daily dose and frequency sought 

for inclusion in labeling and if used chronically, until levels of the active 

ingredient have reached steady state. The amount of test article applied, 

the surface area treated, and the site preparation (e.g., washing) should be 

consistent with proposed directions for use in the OTC monograph.

In general, at least four market image formulations should be tested and should include 

the maximum concentration of the active ingredient proposed for inclusion in the 

applicable OTC monograph. At least one of the formulations tested should include a 

permeation enhancer to evaluate the potential effects of such agents.

The time points for blood sample collection should adequately capture the 

the maximum concentration (Cmax), time to maximum concentration 

(Tmax), and the entire concentration-versus-time profile. The assay used 

in the MUsT should be validated according to current good laboratory 

practices (21 CFR part 58).

When the drug is expected to be used in the geriatric population, a

sufficient number of geriatric subjects should be enrolled in the MUsT

study. Generally, data should be collected in adults first before

considering whether a MUsT is also necessary in children.

Safety Testing MUsT studies should collect safety-related data during the regularly scheduled physical 

examinations and study visits.

≥ 65 and < 18
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about Maximal Usage Trials for Topical Active Ingredients Being Considered for Inclusion in an Over-TheCounter Monograph, read the guidance: https://www.fda.gov/media/125080/download

www.fda.gov

Background About the Guidance

MUsT has been used in the development of topical products in the prescription drug space for over 20 

years. The unique application of the MUsT concept for OTC monographs is that a specific active 

ingredient and not a final drug product/formulation is under consideration. This guidance provides 

important recommendations to sponsors on critical study elements, data analysis, and considerations 

for special topic areas (e.g., pediatrics, geriatrics) for MUsT. The FDA will use information from a MUsT 

to identify the potential for systemic exposure and determine the need for additional safety data to 

support a finding that an OTC product with that active ingredient is generally recognized as safe and 

effective (GRASE) for its intended use. As follow up to publication of the sunscreen proposed rule in 

February 2019, this guidance provides industry with clear direction on how to approach MUsT studies.

Why is this guidance important?

As an example, despite what we know about prevention, skin cancer caused by sun exposure remains 

one of the most common cancers diagnosed in the United States. We know that the use of sunscreens, 

when used with other sun protective measures, is one of our most effective weapons against skin 

cancer. Because sunscreens are designed to work on the surface of the skin, some have proposed that 

sunscreens would not be absorbed in appreciable quantities, making MUsTs unnecessary. However, an 

original research article in the Journal of the American Medical Association found that application of 

6 sunscreen active ingredients from 4 commercially available sunscreens resulted in plasma 

concentrations exceeding the FDA-established threshold for potentially waiving some nonclinical 

toxicology studies for sunscreens.

Drug Development Timeline – 

When to Apply the Guidance Recommendations?

The conduct of a MUsT should be consistent with maximal use 

of the product as specified by existing or anticipated labeling. 

Thus MUsTs for an OTC monograph product should be conducted 

as early as possible once both dosing frequency, amount to be 

applied, target populations, and other relevant factors are 

identified. Such testing should be conducted using multiple 

formulations, including formulations that are designed to 

maximize the potential for absorption. The collected samples 

from the MUsT should then be analyzed, and the systemic 

exposures to the active ingredients of interest should be 

evaluated using standard PK measures. The FDA expects to use 

the resulting in vivo PK data, in conjunction with data from 

animal toxicity studies, to estimate a safety margin for systemic 

exposure to the active ingredient in the relevant category of OTC 

monograph drug products.

During OTC Monograph Development: 

Development Adhering to the OTC Monograph

GRASE 

Determination

Marketing