Maximal Usage Trials for 

Topically Applied Active 

Ingredients Being Considered 

for Inclusion in an Over-The -

Counter Monograph: Study 

Elements and Considerations

Guidance for Industry

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2019

Clinical Pharmacology/Over-the-Counter (OTC)
Maximal Usage Trials for 

Topically Applied Active 

Ingredients Being Considered 

for Inclusion in an Over-TheCounter Monograph: Study 

Elements and Considerations

Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information

Center for Drug Evaluation and Research

Food and Drug Administration

10001New Hampshire Ave., Hillandale Bldg., 4th Floor 

Silver Spring, MD 20993-0002

Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353

Email: druginfo@fda.hhs.gov

https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

May 2019

Clinical Pharmacology/Over-the-Counter (OTC)
Contains Nonbinding Recommendations

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TABLE OF CONTENTS

I. INTRODUCTION......................................................................................................1

II. BACKGROUND ........................................................................................................2

III. MAXIMAL USAGE TRIAL......................................................................................4

A. Overview...................................................................................................................... 4

B. Study Elements and Considerations............................................................................... 5

1. Study Population ........................................................................................................... 5

2. Number of Subjects......................................................................................................... 5

3. Amount Applied.............................................................................................................. 5

4. Surface Area Treated ...................................................................................................... 6

5. Frequency of Dosing....................................................................................................... 6

6. Duration of Dosing......................................................................................................... 7

7. Method of Application..................................................................................................... 7

8. Combinations of Active Ingredients................................................................................... 7

9. Formulation Considerations............................................................................................. 7

10.Sample Collection.......................................................................................................... 8

11.Sensitive and Validated Analytical Method......................................................................... 9

12.Safety Data................................................................................................................... 9

13.Pediatrics..................................................................................................................... 9

14.Geriatrics....................................................................................................................10

IV. DATA ANALYSIS ...................................................................................................10

V. CONSULTATION WITH THE FDA...................................................................... 10
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Maximal Usage Trials for Topically Applied Active Ingredients 

Being Considered for Inclusion in an Over-The-Counter 

Monograph: Study Elements and Considerations

Guidance for Industry1

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 

this topic. It does not establish any rights for any person and is not binding on FDA or the public. You 

can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. 

To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 

title page. 

I. INTRODUCTION 

This guidance provides recommendations for the conduct of in vivo absorption trials for 

topically applied active ingredients that are under consideration for inclusion in an over-thecounter (OTC) drug monograph. A Maximal Usage Trial (MUsT) is a standard approach to 

assess the in vivo bioavailability of topical drug products intended for local therapeutic effects.2,3 

The methodology described in this guidance adapts MUsT principles for active ingredients being 

considered for inclusion in an over-the-counter (OTC) monograph. Because information from a

MUsT can help identify the potential for systemic exposure to a topically applied active 

ingredient, such information can help inform an FDA determination of whether additional safety 

data are needed to support a finding that a topical OTC drug containing that active ingredient is 

generally recognized as safe and effective (GRASE) for its intended use.

This guidance outlines the 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). This guidance also encourages study sponsors to seek 

feedback from the FDA on their overall approach and the design of a particular study.

 1 This guidance has been prepared by the Office of Translational Sciences, Office of Clinical Pharmacology and the 

Office of New Drugs, Division of Nonprescription Products in the Center for Drug Evaluation and Research at the 

Food and Drug Administration. 

2 In this guidance, drug product refers to a finished dosage form, which generally includes both inactive and active 

ingredients. Active ingredient refers to a component of the drug product that provides the intended pharmacological 

activity. 

3 See, for example, the Clinical Pharmacology recommendations in the FDA guidance for industry entitled Head 

Lice Infestation: Developing Drugs for Topical Treatment(October 2016). We update guidances periodically. For 

the most recent version of a guidance, check the FDA guidance web page at 

https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
Contains Nonbinding Recommendations

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In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 

as recommendations, unless specific regulatory or statutory requirements are cited. The use of 

the word should in Agency guidances means that something is suggested or recommended, but 

not required.

II. BACKGROUND

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. 

The principal barrier to cutaneous dermal penetration is the multilayered, lipid-rich stratum 

corneum. The passage of any drug through this layer is influenced by many factors, including 

the drug’s physicochemical characteristics, the properties of the formulation and the vehicle, and 

the condition of the skin (e.g., healthy or diseased). For example, excipients in the drug 

formulation can act as permeation enhancers directly by having solvent effects on the lipids in 

the stratum corneum or indirectly through simple hydration of the stratum corneum by occlusive 

formulations. Products absorbed through the skin have the potential to cause systemic adverse 

effects, affecting the safety assessment. For drugs that are intended to work at the skin’s surface, 

like sunscreens and pediculicides, systemic absorption may also lower efficacy, affecting the 

efficacy assessment. Such considerations ultimately weigh into the risk-benefit calculus the 

FDA uses to determine whether an OTC drug product containing a given active ingredient would 

be GRASE.

Historically, topical treatments were commonly believed not to result in clinically relevant 

systemic drug absorption.4 Even when the potential for systemic absorption of topically applied 

OTC products was recognized,5 the in vivo bioavailability of such products could not always be 

measured because of limitations in analytical methods. As analytical methods advanced, 

however, the FDA started to request pharmacokinetic (PK) trials under maximal-use conditions 

as part of the systemic safety evaluation for topical products developed under the New Drug 

Application (NDA) process. 

 4 Bashaw ED, DC Tran, CG Shukla, X Liu, 2015, Maximal Usage Trial: An Overview of the Design of Systemic 

Bioavailability Trial for Topical Dermatological Products, Ther Innov Regul Sci, 49(1):108-115.

5 See, for example, Benson HA, 2000, Assessment and Clinical Implications of Absorption of Sunscreens Across 

Skin, Am J Clin Dermatol, 1(4):217-24 and Lin YJ, 2000, Buccal Absorption of Triclosan Following Topical 

Mouthrinse Application, Am J Dent, 13(4):215-7.
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The MUsT, also referred to as a maximal-use PK trial, was described in the 2005 FDA draft

guidance for industry Acne Vulgaris: Developing Drugs for Treatment6 and again in 2015 in the 

FDA draft guidance for industry Head Lice Infestation: Developing Drugs for Topical 

Treatment. 7 The MUsT paradigm is now widely used to assess topical drug products developed 

under an NDA. 

Unlike the MUsT paradigm in the NDA context, a MUsT conducted in the OTC monograph 

context evaluates an active ingredient in a range of formulations. This is because an NDA 

review focuses on the safety and effectiveness of a single drug product, i.e., a specified 

formulation of active and inactive ingredients, while the review to establish an OTC monograph 

necessitates determining the conditions under which any of multiple drug products would be 

generally recognized as safe and effective. The resulting monograph authorizes marketing of 

every formulation that meets each of its conditions and complies with other applicable regulatory 

requirements.8 Active ingredients are key conditions in any OTC monograph. However, the 

choice of inactive ingredients, also called excipients, in a finished drug product can affect the 

absorption of the active ingredient. Therefore, before including an active ingredient in an OTC 

monograph, it is important to evaluate the absorption of a representative range of formulations.

In 2014, the FDA asked the Nonprescription Drugs Advisory Committee (NDAC) to address the 

concerns of dermal absorption for sunscreens9 and healthcare antiseptics10 to assist with ongoing 

rulemaking for these topical OTC drugs. Based in part on the committee’s input and 

recommendations, the FDA determined that, in general, results from MUsTs are important to 

support a GRASE determination for topical drugs regulated under an OTC monograph. The 

remainder of this guidance document provides recommendations for the design and conduct of 

such a MUsT. 11

 6 This guidance was finalized in 2018 under the name Acne Vulgaris: Establishing Effectiveness of Drugs Intended 

for Treatment. Because the 2018 guidance was limited in scope to efficacy only, and the MUsT paradigm primarily

relates to safety, the MUsT recommendations(along with other non-efficacy-related portions) were removed from 

the final guidance.

7 This guidance was finalized in 2016 under the same name.

8 See 21 CFR § 330.1.

9 Food and Drug Administration, Center for Drug Evaluation and Research, Summary Minutes of the

Nonprescription Drugs Advisory Committee (NDAC) Meeting, September 4-5, 2014, https://wayback.archiveit.org/7993/20170404152726/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/

Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM421304.pdf

10 Food and Drug Administration, Center for Drug Evaluation and Research, Summary Minutes of the

Nonprescription Drugs Advisory Committee (NDAC) Meeting, September 3, 2014, https://wayback.archiveit.org/7993/20170404152740/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/

Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM421120.pdf

11 Stakeholders have expressed interest in using methods other than the MUsT recommended here to assess 

absorption of active ingredients proposed for use in topical drug products under an OTC drug monograph. We 

recognize that understanding of the dynamics of dermal absorption and the potential of both in vitro and in silico 

models in this area have increased. However, at this time, our recommendations for assessing the absorption of 

proposed monograph ingredients for topical application are limited to use ofMUsTs because, in light ofthe myriad 
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III. MAXIMAL USAGE TRIAL

A. Overview

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. Testing should be conducted using multiple 

formulations, including formulations designed for maximum 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. Routine collection of adverse event 

data is recommended. The need for targeted safety assessments should be considered in the 

protocol design phase. 

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. 12 If the overall record supports a finding 

that a particular category of drugs containing that active ingredient would be GRASE and not 

misbranded under specified monograph conditions, other details from the MUsT may be used to 

establish such conditions to ensure that marketed products remain within an acceptable safety 

margin. For example, if data indicate that there is a need to limit the absorption of a given active 

ingredient, the FDA may consider establishing monograph conditions for final product 

formulations containing that active ingredient, such as in vitro permeation testing for final 

formulations uses as a benchmark the formulation that resulted in the greatest absorption in the 

MUsT for that active ingredient. 

The FDA recognizes that more than one study design can provide the desired information and 

that many factors can influence the specific approach to be used. Study sponsors should seek the 

FDA’s input on the formulations to be tested and other proposed study elements prior to 

conducting the MUsT. The following are the FDA’s general recommendations for the design 

and conduct of the MUsT.

 of possible formulations for OTC products,there is currently insufficient information available to validate 

alternative absorption models for proposed monograph ingredients for topical application. 

As noted at the outset of this guidance document, any person can use an alternative approach to that recommended 

in this guidance if it satisfies the requirements of the applicable statutes and regulations. We urge any sponsorwho 

proposes to use an alternative method toassess absorption of a topically applied active ingredient for purposes of 

supporting a GRASE finding to discuss their proposalwith the FDA, including validation of theirmodel, before

beginning any study.

12 For drugs with a known potential for adverse effects based on animal data, the anticipated level of risk for humans 

may be quantified using a safety margin calculation. A safety margin calculationtakes the highest no-observedadverse-effect level in animals and estimates a maximum safe level of exposure for humans. One caveat to the 

safety margin calculation is that animal studies do not always predict effects in humans, and the actual threshold for 

an effect in humans may be different (higher or lower) than in the species tested. The human sensitivity to a drug is 

often unknown. To account for this uncertainty, the predicted safe exposure level in humans that is reflected in the 

safety margin will be well below the exposure level that causestoxicities in animals.
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B. Study Elements and Considerations

1. Study Population

The study population should be representative of the population expected to use the product. If a 

topical product has more than one indication with different expected populations, the sponsor 

should choose the population with the highest potential for dermal absorption. The resulting data 

may be extrapolated to indications likely to yield lower exposures of the topical drug product. 

Some factors to consider include:13

• Skin surface area to be exposed

• Dosing frequency (if different for different indications)

• Factors affecting skin permeability: For example, if the active ingredient will be used to 

treat a disease where the skin barrier is perturbed (e.g., tinea pedis), the sponsor should 

enroll subjects with the disease of interest to provide an appropriate in vivo assessment of 

the topical drug product’s absorption. If, on the other hand, the topical drug product is to 

be used on healthy skin (e.g., sunscreens or certain antiseptics), the sponsor should enroll 

subjects with healthy, intact skin in the trial. 

2. Number of Subjects

When determining the sample size for a MUsT, the sponsor should consider the study design and 

any potential sources of intersubject and intrasubject variability. The sample size should be large 

enough to provide an estimate of the maximum exposure. Because OTC monographs allow an 

active ingredient to be used in diverse formulations (see section III.B.9), the number of subjects 

needed to create a representative sample will likely be larger than those for PK studies designed 

to support a single drug formulation for an NDA.

If information needed to calculate the number of subjects (such as the expected intersubject and 

intrasubject variability) is not available, the FDA recommends that the sponsor conduct a pilot 

study. This pilot study should use the formulation with the highest potential for permeation 

based on in vitro testing (see section III.B.9). For example, the sponsor could use a formulation 

containing known permeation enhancers in a pilot study. A pilot study can also be used to 

validate the analytical methodology, assess the PK variability, evaluate the time intervals for 

sample collection, and provide other information that can inform the design of the MUsT.14 

While useful in optimizing the study design of a MUsT, a pilot PK study is unlikely to provide 

sufficient data to substitute for a full-scale MUsT.

3. Amount Applied

 13 See sections III.B.13 and III.B.14 for discussions of considerations for pediatric and geriatric populations.

14 See the draft FDA guidance for industry Bioavailability Studies Submitted in NDAs or INDs-General 

Considerations(February 2019). When final, this guidance will represent the FDA’s current thinking on this topic.
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The amount of test article applied should be consistent with the existing or proposed directions 

for use in the applicable OTC monograph. The amount applied should be captured by weighing 

the container or using another appropriate method.

4. Surface Area Treated

The surface area to be treated should be consistent with the intended monograph directions for 

use.

a. Individual lesions

If the drug is proposed for use in skin diseases with specific lesions having defined margins, the 

maximum number of lesions anticipated to be treated at one time should be reflected in the study 

design and be consistent with the proposed use and labeling.

b. Partial-body exposure

In a MUsT evaluating an active ingredient for use in OTC drug products that are applied only to 

part of the human body, the test article should be applied to the maximal area proposed in 

labeling. For example, if the proposed labeling addresses use of the drug product on up to 30 

percent of body surface area, 30 percent of the body should be evaluated in the MUsT.15 The 

surface area of application should be recorded so that it can be submitted in support of a 

monograph determination. For MUsTs evaluating healthcare antiseptics for use as surgical hand 

scrubs, the exposure should cover the hands and arms up to the elbow.

c. Whole-body exposure

If near total-body involvement is a presenting feature of the condition to be treated (e.g., eczema 

in pediatric patients), or if a preventive therapy is intended to be used over a large portion of the 

body (e.g., sunscreen), the test article should be applied to as much body surface area as possible

and appropriate, and the surface area of application should be recorded. For sunscreens, the 

exposed area should include at least 75 percent of the body surface area.

5. Frequency of Dosing

In MUsTs evaluating active ingredients for topical products intended for use multiple times in a 

day, test articles should be administered at the highest frequency sought for inclusion in labeling. 

If the product is intended for application in the morning and at night, then the MUsT should 

incorporate dosing at both times. If the potential monograph labeling recommends re-application 

after specific intervals or activities, the subjects should be redosed accordingly. For example, 

dosing in a MUsT for an antiseptic handrub could entail 100 applications, given that this is the 

 15 Bashaw ED, DC Tran, CG Shukla, X Liu, 2015, Maximal Usage Trial: An Overview of the Design of Systemic 

Bioavailability Trial for Topical Dermatological Products, Ther Innov Regul Sci, 49(1):108-115. See also the FDA 

guidance for industry entitled Head Lice Infestation: Developing Drugs for Topical Treatment (October 2016).
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number of times some health care workers might disinfect their hands in an 8- to 12-hour shift.16 

Dosing in a MUsT for sunscreens should use the same dosing interval as directed in OTC 

sunscreen labeling, every 2 hours.17

6. Duration of Dosing

For active ingredients to be included in OTC drugs that are used chronically, the FDA

recommends that subjects be dosed until levels of the active ingredient and clinically relevant 

metabolites, if any, have reached steady state, both: (1) to ensure that maximum penetration of 

the active ingredient has occurred; and (2) to optimize its chances of being detected. A pilot PK 

study can be useful for determining the duration of dosing in the MUsT.

7. Method of Application

If topical drug products containing the active ingredient of interest bear instructions regarding

application or site preparation (e.g., washing), these same instructions and procedures should be 

incorporated into the MUsT. Likewise, if there are ordinary circumstances surrounding use, such 

as wearing socks or clothing, those conditions should also be incorporated into the MUsT.

8. Combinations of Active Ingredients

In general, the formulation being evaluated in the MUsT should contain the active ingredient

being evaluated for inclusion in an OTC monograph as the only active ingredient. If there is a 

scientific reason for combining more than one active ingredient, sponsors should seek the FDA’s

guidance before initiating a MUsT.

9. Formulation Considerations

Study formulations should have the maximum concentration of the active ingredient proposed 

for inclusion in the applicable OTC monograph.

The FDA recommends that sponsors evaluate multiple formulations in MUsTs because: 

(1) the composition of the formulation may have a large impact on absorption through the 

skin; and (2) active ingredients in OTC monographs may be marketed in multiple diverse 

formulations. Multiple formulations may be evaluated in separate or combined studies. 

The selection of these formulations should be guided by information gained from in vitro 

skin permeation testing using a human cadaver skin permeation system (e.g., static 

cell).18 Justification for the formulations chosen, including results of the in vitro testing, 

 16 Evans V and P Orris, 2012, The Use of Alcohol-Based Hand Sanitizers By Pregnant Health Care Workers, J 

Occup Environ Med, 54(1):3.

17 See 21 CFR 201.327.

18 Casiraghi A, UM Musazzi, P Rocco, S Franzè, P Minghetti, 2016, Topical Treatment of Infantile Haemangiomas: 

A Comparative Study on the Selection of a Semi-Solid Vehicle, Skin Pharmacol Physiol, 29(4):210-9.
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should be included in the MUsT protocol. The protocol should contain sufficient detail 

for others to reproduce the formulations.

In the absence of mitigating safety data or other bioavailability-related information, we 

recommend MUsT testing of at least four formulations. A sponsor that chooses to study 

fewer than four formulations should provide a scientific rationale as well as both in vivo

MUsT and in vitro skin permeation data. Sponsors are encouraged to discuss this 

rationale with the FDA in advance of a monograph submission.

 

The formulations screened in the in vitro skin permeation system and subsequently 

selected for evaluation in a MUsT should be market image formulations with the highest 

potential for absorption of the active ingredient at issue. Market image formulations are

similar to those that would be suitable for marketing in terms of inactive ingredients and 

not, for example, a simple extemporaneous formulation (i.e., a dispersion in a vehicle) 

that was created without regard to such factors as deployability, spreadabilty, and shelflife. These factors, among others, can have a significant impact on absorption.19 In 

addition, because marketed product formulations often include excipients that are known 

permeation enhancers (e.g., alcohol), at least one of the tested formulations should 

include permeation enhancers at the high end of concentrations typically used in topical

OTC drug products.

If an active ingredient is highly absorbed in the first formulation tested and there are gaps 

in the preclinical toxicology safety data that the FDA recommends be gathered to support 

the safety of the active ingredient if absorbed, we recommend that individuals fill in the

nonclinical safety data gaps before evaluating additional formulations. Once supportive 

preclinical toxicology safety data are obtained, additional formulations can be tested as 

necessary to assure that maximum human exposure is adequately defined. On the other 

hand, if important safety risks are detected in preclinical toxicology testing at feasible 

levels of absorption, the active ingredient may not be suitable for the OTC monograph 

system.

10. Sample Collection

The time points for blood sample collection should adequately capture the Cmax, Tmax 20, and the 

entire concentration-versus-time profile. The sponsor should choose time intervals for sample 

collection on the basis of the active ingredient’s known disposition parameters or, in the absence 

of any in vivo information, by using a geometric sampling approach. The time of sample 

collection, the transportation and storage of the sample, and handling techniques of the sample

should be documented. 

 19 Benson HA, 2000, Assessment and Clinical Implications of Absorption of Sunscreens Across Skin, Am J Clin 

Dermatol, 1(4):217-24.

20 Cmax is the peak plasma concentration, and Tmax is the time to peak plasma concentration.
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In general, PK sampling should be collected both after a single dose and at steady state to 

evaluate the accumulation potential of the active ingredient. Additional sampling for the active 

ingredient or metabolite concentrations is also recommended when an adverse event occurs. 

Additionally, sufficient PK sampling after the final dose should be included to ensure proper 

characterization of the terminal elimination rate. A pilot PK study can be useful for informing 

the sample collection considerations for a MUsT.

11. Sensitive and Validated Analytical Method

The use of a validated and sensitive analytical method is scientifically critical. The assay used to 

quantify the blood levels of the analytes of interest from the MUsT should be validated 

according to current good laboratory practices (21 CFR part 58).21 The assay’s limit of 

quantitation should be sufficiently low to allow a signal-to-noise ratio that ensures confidence in 

detection of a compound of interest. To be scientifically sound, the assay needs to be validated 

before study initiation, and the validation results should be part of the study report. If an active 

ingredient has clinically relevant metabolites, an assay should also be developed and validated to 

test for those metabolites. 

12. Safety Data

Study protocols should evaluate the safety and tolerability of the drug product. Because the 

subjects in a MUsT represent an enriched dataset in the upper range of exposures, the FDA 

recommends that the sponsor collect safety-related data (e.g., vital signs, adverse skin events, 

other adverse events) from the study’s regularly scheduled physical examinations and study 

visits.

13. Pediatrics

To assure the safety of pediatric populations, MUsT data should generally be collected in adults 

first before considering whether a MUsT is also necessary in pediatrics. Physiologic and 

development differences between pediatric and adult patients can lead to differences in systemic 

exposure from topically applied products. For example, young children have a larger ratio of 

skin surface-to-body volume compared to adults, which can result in increased systemic 

exposure compared to adults. The skin of young children has significant differences in skin 

capacitance and transepidermal water loss, along with a thinner stratum corneum which can also 

affect systemic absorption. 22 In addition to the potential for increased exposure compared to 

adults, there may be different or more severe adverse effects in children at any given exposure 

level compared to adults because of the effect of a drug on a developing or immature organ 

system. 

 21 See the FDA guidance for industry entitled Bioanalytical Method Validation(May 2018).

22 Nikolovski J, GN Stamatas, N Kollias, and BC Wiegand, 2008, Barrier Function and Water-Holding and 

Transport Properties of Infant Stratum Corneum Are Different From Adult and Continue to Develop Through the 

First Year of Life, J Invest Dermatol, 128(7):1728–36.
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If the calculated safety margin for a proposed monograph active ingredient (based on nonclinical 

results and human MUsT) is relatively small for an adult population, the FDA will determine if 

an additional MUsT in young children or other studies are warranted for any specific pediatric 

age range. There may be other reasons why conducting a MUsT in a pediatric population may 

be needed to support the safety of a proposed monograph active ingredient. Study sponsors 

considering whether to conduct pediatric studies should consult with the FDA. 

14. Geriatrics

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

number of geriatric subjects should be enrolled in the adult MUsT, ensuring adequate 

representation of the entire age range. Geriatric skin is morphologically different from younger 

skin and has less elasticity, moisture content, cellularity, and vascularity. 23, 24, 25

IV. DATA ANALYSIS

If the systemic exposure to the active ingredient is quantifiable, the PK data should be analyzed 

using standard PK metrics for plasma, serum, or blood, such as Cmax, Tmax, area under the curve 

(AUC), half-life, and clearance, which are descriptive of the concentration of the active 

ingredient or its clinically relevant metabolites over time. The accumulation potential of the 

active ingredient should be assessed based on the exposures after single and multiple doses.

The upper range of the systemic exposure (e.g., Cmax, AUC) and their interindividual variances 

among the study population should be reported and will be used to calculate the safety margin 

based on animal toxicity studies. A sufficient number of subjects to give an estimate of the 

maximum exposure is important, as discussed in section III.B. 

V. CONSULTATION WITH THE FDA

We recognize that testing programs are influenced by the specifics of the ingredient, indication, 

prior knowledge, and other factors that cannot be fully addressed in this document. Therefore, 

we encourage study sponsors to seek our advice before initiating a MUsT to support OTC 

monograph status for a particular active ingredient. 

The OTC Drug Review is a public process, culminating in the establishment of OTC drug 

monographs that embody the FDA’s finding that any drug that meets the conditions of that 

monograph and those in 21 CFR 330.1 is GRASE and not misbranded. Such a finding of general 

 23 Luebberding S, N Krueger, and M Kerscher, 2013, Age-Related Changes in Skin Barrier Function—

Quantitative Evaluation of 150 Female Subjects,Int J Cosmet Sci, 35(2):183-90.

24 Luebberding S, N Krueger, and M Kerscher, 2014, Age-Related Changes in Male Skin: Quantitative Evaluation 

of One Hundred and Fifty Male Subjects,Skin Pharmacol Physiol, 27(1):9-17.

25 Farage MA, KW Miller, E Berardesca, and HI Maibach, 2009, Clinical Implications of Aging Skin: Cutaneous 

Disorders in the Elderly,Am J Clin Dermatol, 10(2):73-86.
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recognition needs to be based on data that are generally available, which is ensured by its 

inclusion in the public docket. For this reason, we anticipate that for the FDA to consider a 

MUsT as potential support for the safety of a particular active ingredient, and for its inclusion in 

an OTC drug monograph, that study would need to be included in the public docket for the 

relevant monograph. 

We recognize that sponsors have expressed concern about making certain information about the 

development of their MUsT programs public prematurely, while they are still considering 

whether and how to begin such testing. To address this concern, the FDA may hold private 

meetings with sponsors who request them if they would like to discuss specific potential MUsT 

protocol details that are not yet part of the public record. Notwithstanding the availability of 

such private preliminary meetings, minutes from these meetings are subsequently submitted to 

the public docket and documents submitted for these meetings may be subject to disclosure 

under the Freedom of Information Act. We anticipate that meeting minutes will provide a 

summary of general concepts that were discussed, while excluding information to the extent that 

it contains confidential commercial information, trade secrets, and other types of information at 

this stage of testing that study sponsors generally do not publicly disclose, such as chemistry data 

and detailed protocols. This model gives sponsors the opportunity to privately discuss and 

receive input from the FDA about their preliminary plans to generate the MUsT data needed for 

the FDA to include an active ingredient in a given OTC drug monograph. If a sponsor ultimately 

submits data to support a GRASE determination in an OTC monograph, nothing here will alter 

the obligation to make data that are necessary to support a general recognition determination 

publicly available.