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-The-
Counter 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 
10001 New 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 
 
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 
i  Contains Nonbinding Recommendations 
 
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-the-
counter (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 FDAs 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. 
 
  1  Contains Nonbinding Recommendations 
 
In general, FDAs guidance documents do not establish legally  enforceable responsibilities.   
Instead, guidances describe the Agencys 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 drugs 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 skins 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. 
 
  2  Contains Nonbinding Recommendations 
 
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 committees 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.archive-
it.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.archive-
it.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 of MUsTs because, in light of the myriad 
  3  Contains Nonbinding Recommendations 
 
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 
FDAs input on the formulations  to be tested and other proposed study elements prior to 
conducting the MUsT.  The following  are the FDAs 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 sponsor who 
proposes to use an alternative method to assess absorption of a topically applied active ingredient for purposes of 
supporting a GRASE finding to discuss their proposal with the FDA, including validation of their model, 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 calculation takes the highest no-observed-
adverse-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 causes toxicities in animals. 
  4  Contains Nonbinding Recommendations 
 
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 products 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 FDAs current thinking on this topic. 
  5  Contains Nonbinding Recommendations 
 
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). 
  6  Contains Nonbinding Recommendations 
 
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 FDAs 
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 Franze, 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. 
 
  7  Contains Nonbinding Recommendations 
 
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 shelf-
life.  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 C , T 20,and the 
max max  
entire concentration-versus-time  profile.  The sponsor should choose time intervals for sample 
collection  on the basis of the active ingredients  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 C is the peak plasma concentration, and T is the time to peak plasma concentration. 
max  max 
 
  8  Contains Nonbinding Recommendations 
 
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 assays 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 studys 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):172836.  
 
  9  Contains Nonbinding Recommendations 
 
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 C , T , area under the curve 
max max
(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., C  AUC) and their interindividual  variances 
max,
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 FDAs 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.  
  10  Contains Nonbinding Recommendations 
 
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. 
 
  11