This document discusses the importance of dermal absorption assessments and maximal use trials (MUsT) for topical drug products. It provides background on the evolution of bioavailability testing from pre-1990 approaches to the current standard of MUsT trials. A MUsT is designed to evaluate potential systemic absorption under maximum recommended use conditions and accumulate data on dermal therapeutic responses. Over 20 years, 66 MUsT trials have been conducted on NDAs involving over 1,500 patients. MUsTs are a key part of the FDA review process for both prescription and over-the-counter topical products to determine safety.

1. Dialog and Debate: Personalized Medicine in
Topical Treatments—Relevance of Right
Dose in Right Patient?
Dermal Absorption Assessment &
Implications for Safety

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Disclaimer: The presentation today should
not be considered, in whole or in part as
being statements of policy or
recommendation by the US Food and Drug
Administration.
Throughout the talk or the debate portion of
the program representative examples of
commercial products may be given to
clarify or illustrate a point. No commercial
endorsement is implied or intended.

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Question Based Presentation
• Why do we need to know?
• Is there really a concern?
• Why do we need a standard trial?
• What are the MUsT standard design elements?
• How many have been done?

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Dermal Drug Review
“Paleoregulatory”
Prior to the early 1990s, most topical dermatologicals had
little or no direct assessment of in vivo bioavailability.
Clinical efficacy trials or surrogate markers of drug
absorption were used.
Waivers of in vivo bioavailability testing were the norm and
not the exception
“Personalized dosing” was an unexplored concept

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Dermal Drug Review
“Paleoregulatory”
Clinical Trials
Direct assessment of clinical utility
Relatively long duration to see maximal benefit in
patients
Surrogate Markers
Often provide an assessment not of efficacy but of
safety (i.e. HPA Axis suppression)
Often no correlation between marker
(vasoconstriction) and therapeutic benefit

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Common Features of In Vivo Dermal
Bioavailability Studies
pre-1990
• Study done in subjects with healthy skin
• Study done on small surface areas
• Study done with inadequate analytical methods
• Study done with too few subjects
• Study done as a single dose study
The information gained from such studies was inadequate
for any attempts at PATIENT based individualization

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Why Do We Need to Know?
It has been the lack of an ability to assess local drug
concentrations and a lack of correlation between
systemic levels and local therapeutic effect that has
required the use of clinical trials to assess
bioavailability.
http://www.nku.edu/~dempseyd/SKIN.htm

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Bioavailability
21 CFR § 320.1 Definitions.
(a) Bioavailability means the rate and extent to
which the active ingredient or active moiety is
absorbed from a drug product and becomes
available at the site of action.

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Peripheral
Compartment
Central
Compartment
Effect
Site
?
The Riddle of “Effect Site” Concentrations
for a Topically Acting Drug
Topical
Application
Stratum Corneum

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Determinants of Topical Bioavailability
Drug
Substance
Technolog
y
Skin
Factors
Bioavailabilit
y
It is the complex interaction of
drug substance, formulation-
dosage form, and those skin
factors that affect the barrier
function of the skin that
determines systemic drug
availability, its profile over
time, and product design
selection, ie., personalization!

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Is There Really a Concern?
Sunscreen as a Model
• Conventional wisdom was that
topical products were not
absorbed.
• Any absorption was considered
insignificant
• However, analytical technology
finally caught up with the
problem in the 1990s.
• Experience with modern
analytical methods has shown
that topically applied products
do reach the systemic circulation
and can have biologic effects
(safety related)

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Sunscreen Absorption
Data was collected from 54 women who gave birth at the University
Women’s Hospital Basel between 2004 and 2006 during the
corresponding summer-late fall. The majority women self-reported
some use of sunscreen containing cosmetics during the time periods
before and after delivery.

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The Maximal Use Trial
In the mid 1990s the FDA developed and implemented the
use of the “maximal use” trial as part of an in vivo
bioavailability program.
Outgrowth of the dissatisfaction with previous bioavailability
assessments
Made possible by the refinement of analytical methodologies
Trial design has been presented and discussed at various
national meetings and workshops (AAPS, FIP-
BioInternational, ASCPT, etc.)

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Published in the Scientific Literature

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The Maximal Usage Trial
Designed to evaluate the potential for systemic
drug absorption at the upper limit of use
covered by the clinical trials and allowed for in
the label in the patient population of interest.
While it has been successful in developing
better assessments of systemic exposure and
safety issues, it is still limited in its ability to
assess bioavailability, per se.
Not designed for personalization but to aid in
safety assessment

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The Maximal Usage Trial
Limited in that it does have a “1 approach fits all”
connotation
Even so it does address the earlier shortcomings of
dermatologic research
It does not itself inform “personalized” dosing, but it is a first
step beyond pure clinical endpoint studies
Does NOT represent the end of FDA thought on dermal
drug development.
Technology evolves
New Methods and New Sciences (nanotechnology)
 FDA’s methods will have to evolve as well
The FDA cannot do it alone-nor does it want to

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The PRIMARY Value of a MUsT-
NDA or OTC?
It allows for the linkage of human exposure data under “full-
dose” conditions back to pre-clinical safety studies.
Allows for estimation of safety margins relative to pre-clinical markers
It starts to accumulate the information needed to start
mapping out dermal therapeutic response in a more controlled
setting
It represents a standardized trial design that can be used for
formulation optimization studies (NDA or OTC).

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NDA Product Monograph INGREDIENT
Key Difference Between NDA
and OTC (Monograph) Products

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2nd Annual Student Intern Science Poster
How Many Have Been Done?

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MUsT Survey 1996-2016
Original NDAs Only
• A total of 66 MUsT trials have been conducted over 20yrs
– An additional 20-30 trials have also been submitted as part of supplements
• Of the 66 trials they enrolled 1,545 patients
– 887(58.6%) Male and 658(43.4%) Female

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MUsT in NDA Guidances #1
Actually this is an update to a 1996 guidance that ALSO had the MUsT in it.

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MUsT in NDA Guidances #2

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Maximum Use Trial
“Standard Language”
It has been the Agency's policy to request that a maximal usage trial be undertaken in a
suitable number of subjects with the dermatological disease of interest at the upper
range of severity as anticipated in both your clinical trials and proposed labeling. Such a
trial would attempt to maximize the potential for drug absorption to occur by
incorporation of the following design elements:
a) Frequency of dosing
b) Duration of dosing
c) Use of highest proposed strength
d) Total involved surface area to be treated at one time
e) Amount applied per square centimeter
f) Method of application/site preparation
The trial itself could be a stand alone trial in phase II or could be a sub-group of subjects
in a larger phase III trial. Either approach is acceptable and has been used successfully
by other sponsors

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MUsT in OTC Safety and Efficacy
Guidance for Sunscreens
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM473464.pdf

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Conclusions
MUsT in the Review Process
MUsT is a key component of the safety determination
process for an OTC NDA, an OTC monograph product
or a NDA.
The design elements were chosen to MAXIMIZE the
ability of the study to detect in vivo blood levels
independent of it being for an NDA product or an OTC
active ingredient.

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Conclusions
Since the mid-1990s, topically applied products,
for local use, approved under an NDA have had an
assessment of in vivo bioavailability testing under
“maximal use” conditions
For OTC topical products the same MUsT paradigm
provides equally important data linking back to
pre-clinical safety studies for the qualification of
new INGREDIENTS.

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WHO?
• Edward Dennis Bashaw
• Jonathan Wilkin
• Tapash Ghosh
• Abi Adebowale
• Chinmay Shukla
• Doanh Tran
• Xiaomei Liu
• Brenda Gierhart
• Luke Oh
• Sojeong Yi
• Da Zhang